Inhibitors of janus kinases

ABSTRACT

The instant invention provides for tetracyclic compounds that inhibit the four known mammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2) and PDK1. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting the activity of JAK1, JAK2, JAK3 TYK2 and PDK1 by administering the compound to a patient in need of treatment for myeloproliferative disorders or cancer.

PRIORITY CLAIM

This application is a §371 National Stage Application ofPCT/US2007/013255 filed on Jun. 5, 2007, which claims priority from U.S.Provisional Application Ser. No. 60/812,524, filed on Jun. 9, 2006.

BACKGROUND OF THE INVENTION

Janus kinase (JAK) is a family of intracellular non-receptor tyrosinekinases, ranging from 120-140 kDa, that transduce cytokine-mediatedsignals via the JAK-STAT pathway. The JAK family plays a role in thecytokine-dependent regulation of proliferation and function of cellsinvolved in immune response. Currently, there are four known mammalianJAK family members: JAK1, JAK2, JAK3 and TYK2.

JAK1, JAK2 and TYK2 are ubiquitously expressed whereas JAK3 is expressedin the myeloid and lymphoid lineages. The JAK family members arenon-receptor tyrosine kinases that associate with many hematopoietincytokines, receptor tyrosine kinases and GPCR's. JAK1−/− mice were foundto be developmentally similar to the JAK1+/+ although they weighed 40%less than the wild-type and failed to nurse at birth. These pups werenot viable and died within 24 hours of birth (Meraz et al Cell, 1998,373-383). JAK1 deficiency led to reduced number of thymocytes, pre-Bcells and mature T and B lymphocytes. TYK2(−/−) mice, on the other hand,are viable, demonstrating subtle defects in their response to IFN-α/βand IL-10 and profound defects to the response of IL-12 and LPS.

The breast cancer susceptibility protein (BRCA1) acts as a tumorsuppressor and contributes to cell proliferation, cycle regulation, aswell as DNA damage and repair. BRCA1 (−/−) mice develop normally but dieby 7.5 days post embryo suggesting a key role of BRCA1 for development.Mice in which the BRCA1 protein was overexpressed led to inhibition ofcell growth and sensitized cells to cytotoxic reagents. In the humanprostate cancer cell line Du-145(Gao FEBS Letters 2001, 488, 179-184),enhanced expression of BRCA1 was found to correlate with constitutiveactivation of STAT3 as well as activation of JAK1 and JAK2. Moreover,antisense oligonucleotides selective for STAT3 led to significantinhibition of cell proliferation and apoptosis in Du-145 cells. Thisdata supports the potential utility of JAK1 and JAK2inhibitors in thetreatment of prostate cancer.

Campbell et al (Journal of Biological Chemistry 1997, 272, 2591-2594) asreported that STAT3 is constitutively activated v-Src transformed cells.To test whether STAT3activation resulted via signaling through theJAK-STAT pathway, three fibroblast cell lines (NIH3T3, Balb/c, and 3Y1)were transformed with v-Src. The level of JAK1 phosphorylation in NIH3T3cells was markedly increased in cells overexpressed with v-Src or mutantc-Src (Y527F) compared to those in the less transforming c-Src. Thisresult correlated with increased JAK1 enzymatic activity. Similarresults were observed with JAK2 albeit to a lesser extent. These resultsare consistent with constitutive activation of JAK1 and possibly JAK2which contribute to the hyperactivation of STAT3 in Src-transformedcells.

Asthma is a disease that is increasing in prevalence and results in“airway obstruction, airway hyperresponsiveness, and airway inflammationand remodeling” (Pernis The Journal of Clinical Investigation 2002, 109,1279-1283). A common cause is the inappropriate immune responses toenvironmental antigens usually involving CD4+ T helper cells (TH2) whichare triggered from cytokines IL-4, IL-5, IL-6, IL-10, and IL-13 whichsignal through JAK1/JAK3-STAT6 pathway. Th1 cells are thought to beinvolved with the “delayed-type hypersensitivity responses” whichsecrete IL-2, IFN-γ, and TNF-β and signal through the JAK2/TYK2-STAT4pathway. STAT6 (−/−) mice were protected from AHR when challenged withenvironmental antigens and showed no increase in IgE levels or thequantity of mucous containing cells.

JAK2 is a cytoplasmic protein-tyrosine kinase that catalyzes thetransfer of the gamma-phosphate group of adenosine triphosphate to thehydroxyl groups of specific tyrosine residues in signal transductionmolecules. JAK2 mediates signaling downstream of cytokine receptorsafter ligand-induced autophosphorylation of both receptor and enzyme.The main downstream effectors of JAK2 are a family of transcriptionfactors known as signal transducers and activators of transcription(STAT) proteins. Studies have disclosed an association between anactivating JAK2 mutation (JAK2V617F) and myleoproliferative disorders.The myeloproliferative disorders, a subgroup of myeloid malignancies,are clonal stem cell diseases characterized by an expansion ofmorphologically mature granulocyte, erythroid, megakaryocyte, ormonocyte lineage cells. Myeloproliferative disorders (MPD) includepolycythemia vera (PV), essential thrombocythemia (ET), myeloidmetaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML),chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome(HES), juvenile myelomonocytic leukemia (JMML) and systemic mast celldisease (SMCD). It has been suggested that abnormalties in signaltransduction mechanisms, including constitutive activation of proteintyrosine kinases, initiate MPD.

JAK3 associates with the common gamma chain of the extracellularreceptors for the following interleukins: IL-2, IL-4, IL-7, IL-9 andIL-15. A JAK3 deficiency is associated with an immune compromised (SCID)phenotype in both rodents and humans. The SCID phenotype of JAK3 −/−mammals and the lymphoid cell specific expression of JAK3 are twofavorable attributes of a target for an immune suppressant. Datasuggests that inhibitors of JAK3could impede T-cell activation andprevent rejection of grafts following transplant surgery, or to providetherapeutic benefit to patients suffering autoimmune disorders.

PDK1 signalling regulates multiple critical steps in angiogenesis.Inhibitors of the activity of PDK1 are thus useful in the treatment ofcancer, in particular cancers associated with deregulated activity ofthe PTEN/P13K pathway including, but not limited to PTEN loss offunction mutations and receptor tyrosine kinase gain of functionmutations.

SUMMARY OF THE INVENTION

The instant invention provides for compounds that inhibit the four knownmammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2) and PDK1. Theinvention also provides for compositions comprising such inhibitorycompounds and methods of inhibiting the activity of JAK1, JAK2, JAK3TYK2 and PDK1 by administering the compound to a patient in need oftreatment for myeloproliferative disorders or cancer. One embodiment ofthe invention is illustrated by a compound of the following formula, andthe pharmaceutically acceptable salts and stereoisomers thereof:

DETAILED DESCRIPTION OF THE INVENTION

The instant invention provides for compounds that inhibit the four knownmammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2) and PDK1. Theinvention also provides for compositions comprising such inhibitorycompounds and methods of inhibiting the activity of JAK1, JAK2, JAK3,TYK2 and PDK1 by administering the compound to a patient in need oftreatment for myeloproliferative disorders or cancer. One embodiment ofthe invention is illustrated by a compound of the formula

wherein R¹ is aryl, heteroaryl, heterocyclyl, C₃₋₈ cycloalkyl, or C₁₋₆alkyl, wherein said aryl, heteroaryl, heterocyclyl, cycloalkyl and alkylgroups are optionally substituted with one to three substituentsindependently selected from the group consisting of halo, hydroxyl,C₁₋₆alkyl, O(C₁₋₆alkyl), R³ and halolakyl;

-   R² is aryl, heteroaryl, heterocyclyl, C₃₋₈ cycloalkyl, halo,    C₁₋₆alkyl, (C═O)R³, (C═O)NR⁴(C₁₋₆alkyl)R³, (C═O)NR⁴SO_(m)C₁₋₆alkyl,    (C═O)NR⁴(C₁₋₆alkyl)NR⁴R⁵, NR⁴⁻(C₁₋₆alkyl)-R³, NR⁴(C₁₋₆alkyl)OR⁵,    NR⁴(C₁₋₆alkyl)NR⁴R³, NR⁴R⁵, NR⁴R³ or NR⁴SO_(m)NR⁴R⁵, wherein said    aryl, heteroaryl, heterocyclyl, cycloalkyl and alkyl groups are    optionally substituted with one to three substituents independently    selected from the group consisting of R³, hydroxyl, cyano, halo,    C₁₋₆alkyl, O(C₁₋₆alkyl), O(C₁₋₆alkyl)R³, (C₁₋₆alkyl)R³, (C═O)R³,    OR³, (C═O)R³H, (C═O) R³O(C₁₋₆alkyl), (C═O)O(C₁₋₆alkyl),    R³(C═O)O(C₁₋₆alkyl), SO_(m)R³, SO_(m)R⁴, (C═O)NR⁴R⁵,    (C═O)NR⁴(C₁₋₆alkyl)R³; (C═O)NR⁴(C₁₋₆alkyl)NR⁴R⁵, (C═O)O(C₁₋₆alkyl),    (C═O)NR⁴SO_(m)(C₁₋₆alkyl), NR⁴R⁵, (C═O)NR⁴R⁵, N(R³)₂,    NR⁴(C₁₋₆alkyl)R³, NR⁴(C═O)C₁₋₆alkyl, NR⁴SO_(m)(C₁₋₆alkyl),    (C₁₋₆alkyl)NR⁴R⁵ and NHSO_(m) N(R³)₂;-   each R³ is independently aryl, heteroaryl, heterocyclyl or C₃₋₈    cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl and    cycloalkyl groups are optionally substituted with one to three halo,    hydroxyl or C₁₋₆ alkyl;-   R⁴ is hydrogen or C₁₋₆ alkyl;-   R⁵ is hydrogen or C₁₋₆ alkyl;-   m is an integer from zero to two;-   or a pharmaceutically acceptable salt or a stereoisomer thereof.

In an embodiment of the invention, R¹ is aryl or heteroaryl, whereinsaid aryl and heteroaryl groups are optionally substituted with one tothree halo. In a class of the embodiment, R¹ is phenyl or pyridyl,wherein said phenyl and pyridyl groups are optionally substituted withone to three halo. In a subclass of the embodiment, R¹ is phenylsubstituted with two halo.

In an embodiment of the invention, R² is heteroaryl, heterocyclyl,NR⁴(C₁₋₆alkyl)R³, NR⁴(C₁₋₆alkyl)OR⁵, NR⁴(C₁₋₆alkyl)NR³, NR⁴R⁵ orNR⁴SO_(m)NR⁴R⁵, wherein said heteroaryl, heterocyclyl and alkyl groupsare optionally substituted with one to three substituents independentlyselected from the group consisting of R³, hydroxyl, cyano and halo. In aclass of the embodiment, R² is heteroaryl, NR⁴(C₁₋₆alkyl)R³,NR⁴(C₁₋₆alkyl)OR⁵ or NR⁴R⁵ wherein said heteroaryl and alkyl groups areoptionally substituted with one to three substituents independentlyselected from the group consisting of hydroxyl, cyano and halo. In asubclass of the embodiment, R² is heteroaryl wherein said heteroaryl andalkyl group is optionally substituted with one to two substituentsindependently selected from the group consisting of hydroxyl, cyano andhalo. In a further subclass of the invention, R² is pyridinyl whereinsaid pyridinyl group is optionally substituted with one to twosubstituents independently selected from the group consisting of cyanoand halo.

Reference to the preferred embodiments set forth above is meant toinclude all combinations of particular and preferred groups unlessstated otherwise.

Specific embodiments of the present invention include, but are notlimited to:

-   9-bromo-2-(2-chloro-6-fluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-cyclopentyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-(2-chlorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-(isobutylamino)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-N-[2-(dimethylamino)ethyl]-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinoline-9-carboxamide;-   2-cyclopentyl-9-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(6-chloropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   N′-[2-(2-chloro-6-fluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-4-yl]-N,N-dimethylsulfamide;-   2-(2,6-difluorophenyl)-9-[(tetrahydrofuran-3-ylmethyl)amino]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-(5-chloropyridin-2-yl)-2-(2,6-difluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(2,6-difluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-(2-chlorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-(tetrahydrofuran-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-(tetrahydro-2H-pyran-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-(2,2-dimethyltetrahydro-2-H-pyran-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-(1-isopropyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-pyridin-3-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5f]isoquinolin-7-one;-   9-bromo-2-(1,5-dimethyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-isoquinolin-8-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-isoquinolin-5-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-cyclopentyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-(2-chloro-6-fluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-(3-chloropyridin-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-(1-phenylethyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-(2-chloro-4-fluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-(2,4,6-trifluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-(2,6-difluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-bromo-2-(trifluoromethyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-(isobutylamino)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-{[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]amino}-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-{[1-(4-chlorophenyl)ethyl]amino}-2-cyclopentyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-[(tetrahydrofuran-2-ylmethyl)amino]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-[(2-methoxyethyl)amino]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-[(2-hydroxy-2-phenylethyl)(methyl)amino]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-[(2R)-2-phenylmorpholin-4-yl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-[(3R)-3    -methoxypyrrolidin-1-yl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2,6-difluorophenyl)-9-[(tetrahydrofuran-2-ylmethyl)amino]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   N′-[2-(2-chloro-6-fluorophenyl)-7-oxo-6,7-dihydro-1H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]-N,N-dimethylsulfamide;-   2-(2,6-difluorophenyl)-9-{[(3    -methyloxetan-3-yl)methyl]amino}-3,6-dihydro-7H-benzo[h]imidazo[4,5f]isoquinolin-7-one;-   2-(2,6-difluorophenyl)-9-[(tetrahydrofuran-3-ylmethyl)amino]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2,6-difluorophenyl)-9-{[(2-methyltetrahydrofuran-2-yl)methyl]amino}-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2,6-difluorophenyl)-9-[(1,4-dioxan-2-ylmethyl)amino]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   3-{[2-(2,6-difluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]amino}propanenitrile;-   2-(2,6-difluorophenyl)-9-{[2-(1H-imidazol-4-yl)ethyl]amino}-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-[(2,4-difluorobenzyl)amino]-2-(2,6-difluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2,6-difluorophenyl)-9-{[2-(pyridin-2-ylamino)ethyl]amino}-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2,6-difluorophenyl)-9-[(2,3-dihydroxypropyl)amino]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chlorophenyl)-9-pyridin-4-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   tert-butyl    4-{4-[2-(2-chlorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]phenyl}piperazine-1-carboxylate;-   2-(2-chlorophenyl)-9-(4-piperazin-1-ylphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chlorophenyl)-9-[3-(dimethylamino)phenyl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-biphenyl-3-yl-2-(2-chlorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-biphenyl-2-yl-2-(2-chlorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chlorophenyl)-9-pyridin-3-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   4-[2-(2-chlorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]-N,N-dimethylbenzamide;-   4-[2-(2-chlorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9yl]-N-[2-(dimethylamino)ethyl]benzamide;-   2-(2-chlorophenyl)-9-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3,6-dihydro-7H-benzo[h]imidazo[4,5    -f]isoquinolin-7-one;-   2-(2-chlorophenyl)-9-[2-(4-methylpiperazin-1yl)pyridin-4-yl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chlorophenyl)-9-[4-(morpholin-4-ylcarbonyl)phenyl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   N-{3-[2-(2-chlorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]phenyl}methanesulfonamide;-   N-{4-[2-(2-chlorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]phenyl}methanesulfonamide;-   2-(2-chlorophenyl)-9-(4-methoxyphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chlorophenyl)-9-(3-methoxyphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chlorophenyl)-9-(2-methoxyphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   4-[2-(2-chlorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5f]isoquinolin-9-yl]-N-ethylbenzamide;-   4-[2-(2-chlorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]-N-isobutylbenzamide;-   2-(2-chlorophenyl)-9-quinolin-5-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chlorophenyl)-9-(1H-pyrazol-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chlorophenyl)-9-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-(1H-pyrazol-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-[4-(morpholin-4-ylcarbonyl)phenyl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-(1H-pyrazol-3-yl)-2-(tetrahydrofuran-3yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-N-[2-(dimethylamino)ethyl]-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinoline-9-carboxamide;-   2-cyclopentyl-N-(3-methylbutyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinoline-9-carboxamide;-   2-cyclopentyl-9-[(4-methylpiperazin-1-yl)carbonyl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-(morpholin-4-ylcarbonyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-[(4-hydroxypiperidin-1-yl)carbonyl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-(piperidin-1-ylcarbonyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-7-oxo-N-(pyridin-2-ylmethyl)-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinoline-9-carboxamide;-   2-cyclopentyl-7-oxo-N-(pyridin-3-ylmethyl)-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinoline-9-carboxamide;-   2-cyclopentyl-N-(methylsulfonyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinoline-9-carboxamide;-   N-benzyl-2-cyclopentyl-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinoline-9-carboxamide;-   9-(1H-pyrazol-3-yl)-2-(tetrahydrofuran-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-(6-methoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-(1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-(2,6-dimethoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-pyrimidin-5-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-cyclopentyl-9-(3,5-dimethylisoxazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(1H-pyrazol-3-yl)-1,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-pyridin-3    -yl-1,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(4-morpholin-4-ylphenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(2-morpholin-4-ylpyridin-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-pyridin-4-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-(6-aminopyridin-3-yl)-2-(2-chloro-6-fluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(6-methoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(4-methoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-{6-[(2-morpholin-4-ylethyl)amino]pyridin-3-yl)}-3,6-dihydro-7H-benzo[h]imidazo[4,5f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(6-hydroxypyridin-3yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(5-chloro-2-methoxypyridin-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(6-chloropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   N-{3-[2-(2-chloro-6-fluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]pyridin-2-yl}-2,2-dimethylpropanamide;-   2-(2-chloro-6-fluorophenyl)-9-[2-(cyclopropylmethoxy)pyridin-3yl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(6-fluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   5-[2-(2-chloro-6-fluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]pyridine-2-carbonitrile;-   2-(2-chloro-6-fluorophenyl)-9-(2,6-difluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(6-methylpyridin-3yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-pyrimidin-5-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-quinolin-3-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-[6-(dimethylamino)pyridin-3-yl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(3-furyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-(4-aminophenyl)-2-(2-chloro-6-fluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-(3-aminophenyl)-2-(2-chloro-6-fluorophenyl)-3,6-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-[4-(dimethylamino)phenyl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-{2-[(dimethylamino)methyl]phenyl}-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(2,6-dimethoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(3,5-dimethyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7    -one;-   2-(2-chloro-6-fluorophenyl)-9-(1,3,5-trimethyl-1H-pyrazol-4yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-isoquinolin-4-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(2-methoxypyrimidin-5-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(6-morpholin-4-ylpyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(2-methoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2-chloro-6-fluorophenyl)-9-(2-fluoroquinolin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   N-{3-[2-(2-chloro-6-fluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]phenyl}acetamide;-   N-{3-[2-(2-chloro-6-fluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]phenyl}methanesulfonamide;-   N-{4-[2-(2-chloro-6-fluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]phenyl}methanesulfonamide;-   3-[2-(2-chloro-6-fluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]benzamide;-   4-[2-(2-chloro-6-fluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]benzamide;-   2-(2,6-difluorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2,6-difluorophenyl)-9-(6-fluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2,6-difluorophenyl)-9-(3,4-difluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   4-[2-(2,6-difluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]-2-fluorobenzonitrile;-   2-(2,6-difluorophenyl)-9-(2,3,4-trifluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2,6-difluorophenyl)-9-(2-fluoropyridin-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2,6-difluorophenyl)-9-(5-fluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-2,6-difluorophenyl)-9-(5-fluoropyridin-2-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2,6-difluorophenyl)-9-(3-fluoropyridin-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one,-   9-(2-chloropyridin-4-yl)-2-(2,6-difluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2,6-difluorophenyl)-9-(6-fluoropyridin-2-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-(5-chloropyridin-2-yl)-2-(2,6-difluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2,6-difluorophenyl)-9-(6-methoxypyridin-2-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   2-(2,6-difluorophenyl)-9-pyridin-2-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-(1-methyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-2-(trifluoromethyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   9-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-2-(trifluoromethyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;-   or a pharmaceutically acceptable salt or stereoisomer thereof.

Also included within the scope of the present invention is apharmaceutical composition which is comprised of a compound of Formula Ias described above and a pharmaceutically acceptable carrier. Theinvention is also contemplated to encompass a pharmaceutical compositionwhich is comprised of a pharmaceutically acceptable carrier and any ofthe compounds specifically disclosed in the present application. Theseand other aspects of the invention will be apparent from the teachingscontained herein.

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, all such stereoisomers beingincluded in the present invention.

In addition, the compounds disclosed herein may exist as tautomers andboth tautomeric forms are intended to be encompassed by the scope of theinvention, even though only one tautomeric structure is depicted. Forexample the following is within the scope of the instant invention:

Imidazoles exist as a mixture of 1H/2H tautomers. The tautomeric formsof the imidazole moiety are also within the scope of the instantinvention.

When any variable (e.g. R³, etc.) occurs more than one time in anyconstituent, its definition on each occurrence is independent at everyother occurrence. Also, combinations of substituents and variables arepermissible only if such combinations result in stable compounds. Linesdrawn into the ring systems from substituents represent that theindicated bond may be attached to any of the substitutable ring atoms.If the ring system is bicyclic, it is intended that the bond be attachedto any of the suitable atoms on either ring of the bicyclic moiety.

It is understood that one or more silicon (Si) atoms can be incorporatedinto the compounds of the instant invention in place of one or morecarbon atoms by one of ordinary skill in the art to provide compoundsthat are chemically stable and that can be readily synthesized bytechniques known in the art from readily available starting materials.Carbon and silicon differ in their covalent radius leading todifferences in bond distance and the steric arrangement when comparinganalogous C-element and Si-element bonds. These differences lead tosubtle changes in the size and shape of silicon-containing compoundswhen compared to carbon. One of ordinary skill in the art wouldunderstand that size and shape differences can lead to subtle ordramatic changes in potency, solubility, lack of off target activity,packaging properties, and so on. (Diass, J. O. et al. Organometallics(2006) 5:1188-1198; Showell, G. A. et al. Bioorganic & MedicinalChemistry Letters (2006) 16:2555-2558).

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted with one or more substituents” shouldbe taken to be equivalent to the phrase “optionally substituted with atleast one substituent” and in such cases the preferred embodiment willhave from zero to four substituents, and the more preferred embodimentwill have from zero to three substituents.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁-C₁₀ as in“(C₁-C₁₀)alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7,8, 9 or 10 carbons in a linear or branched arrangement. For example,“(C₁-C₁₀)alkyl” specifically includes methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,and so on.

The term “cycloalkyl” means a monocyclic saturated aliphatic hydrocarbongroup having the specified number of carbon atoms. For example,“cycloalkyl” includes cyclopropyl, methyl-cyclopropyl,2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on.

The term “haloalkyl” means an alkyl radical as defined above, unlessotherwise specified, that is substituted with one to five, preferablyone to three halogen. Representative examples include, but are notlimited to trifluoromethyl, dichloroethyl, and the like.

“Alkoxy” represents either a cyclic or non-cyclic alkyl group ofindicated number of carbon atoms attached through an oxygen bridge.“Alkoxy” therefore encompasses the definitions of alkyl and cycloalkylabove.

In certain instances, substituents may be defined with a range ofcarbons that includes zero, such as (C₀-C₆)alkyl-aryl. If aryl is takento be phenyl, this definition would include phenyl itself as well as—CH₂Ph, —CH₂CH₂Ph, CH(CH₃)CH₂CH(CH₃)Ph, and so on.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 atoms in each ring, wherein at least onering is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydro-naphthyl, indanyl and biphenyl. In cases where thearyl substituent is bicyclic and one ring is non-aromatic, it isunderstood that attachment is via the aromatic ring.

The term “heteroaryl,” as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S. Heteroaryl groups within the scope of thisdefinition include but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl,thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrahydroquinoline. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively. Suchheteraoaryl moieties for substituent Q include but are not limited to:2-benzimidazolyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl,1-isoquinolinyl, 3-isoquinolinyl and 4-isoquinolinyl.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 3- to 10-membered aromatic or nonaromatic heterocycle containingfrom 1 to 4 heteroatoms selected from the group consisting of O, N andS, and includes bicyclic groups. “Heterocyclyl” therefore includes theabove mentioned heteroaryls, as well as dihydro and tetrathydro analogsthereof. Further examples of “heterocyclyl” include, but are not limitedto the following: benzoimidazolyl, benzoimidazolonyl, benzofuranyl,benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro (Cl), fluoro (F), bromo (Br) andiodo (I).

Included in the instant invention is the free form of compounds of theinstant invention, as well as the pharmaceutically acceptable salts andstereoisomers thereof. Some of the isolated specific compoundsexemplified herein are the protonated salts of amine compounds. The term“free form” refers to the amine compounds in non-salt form. Theencompassed pharmaceutically acceptable salts not only include theisolated salts exemplified for the specific compounds described herein,but also all the typical pharmaceutically acceptable salts of the freeform of compounds of the instant invention. The free form of thespecific salt compounds described may be isolated using techniques knownin the art. For example, the free form may be regenerated by treatingthe salt with a suitable dilute aqueous base solution such as diluteaqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. Thefree forms may differ from their respective salt forms somewhat incertain physical properties, such as solubility in polar solvents, butthe acid and base salts are otherwise pharmaceutically equivalent totheir respective free forms for purposes of the invention.

The pharmaceutically acceptable salts of the instant compounds can besynthesized from the compounds of this invention which contain a basicor acidic moiety by conventional chemical methods. Generally, the saltsof the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of thisinvention include the conventional non-toxic salts of the compounds ofthis invention as formed by reacting a basic instant compound with aninorganic or organic acid. For example, conventional non-toxic saltsinclude those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, aswell as salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic(TFA) and the like.

When the compound of the present invention is acidic, suitable“pharmaceutically acceptable salts” refers to salts prepared formpharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betainecaffeine, choline, N,N¹-dibenzylethylenediamine, diethylamin,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylaminetripropylamine, tromethamine and the like.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977:66:1-19.

It will also be noted that the compounds of the present invention arepotentially internal salts or zwitterions, since under physiologicalconditions a deprotonated acidic moiety in the compound, such as acarboxyl group, may be anionic, and this electronic charge might then bebalanced off internally against the cationic charge of a protonated oralkylated basic moiety, such as a quaternary nitrogen atom.

Utility

The compounds of the present invention are inhibitors of JAK 1, JAK2,JAK 3, TYK2 and PDK1, and are therefore useful to treat or preventmyeloproliferative disorders or cancer in mammals, preferably humans.

An embodiment of the invention provides a method for inhibiting JAK1tyrosine kinase, comprising administering to the mammal atherapeutically effective amount of any of the compounds or any of thepharmaceutical compositions described above.

An embodiment of the invention provides a method for inhibiting JAK2tyrosine kinase, comprising administering to the mammal atherapeutically effective amount of any of the compounds or any of thepharmaceutical compositions described above.

An embodiment of the invention provides a method for inhibiting wildtype or mutant JAK2 tyrosine kinase, comprising administering to themammal a therapeutically effective amount of any of the compounds or anyof the pharmaceutical compositions described above.

An embodiment of the invention provides a method for inhibitingJAK2V617F tyrosine kinase, comprising administering to the mammal atherapeutically effective amount of any of the compounds or any of thepharmaceutical compositions described above.

The compounds, compositions and methods provided herein are particularlydeemed useful for the treatment of myeloproliferative disorder(s).Myeloproliferative disorders that may be treated include polycythemiavera (PV), essential thrombocythemia (ET), myeloid metaplasia withmyelofibrosis (MMM), chronic myelogenous leukemia (CML), myelomonocyticleukemia (CMML), hypereosinophilic syndrome (HES), juvenilemyelomonocytic leukemia (JMML), and systemic mast cell disease (SMCD).

It is known in the literature that inhibitors of JAK2 are useful in thetreatment and/or prevention of myeloproliferative disorders. See, e.g.,Tefferi, A. and Gilliland, D. G. Mayo Clin. Proc. 80(7): 947-958 (2005);Fernandez-Luna, J. L. et al. Haematologica 83(2): 97-98 (1998);Harrison, C. N. Br. J. Haematol. 130(2): 153-165 (2005); Leukemia (2005)19, 1843-1844; and Tefferi, A. and Barbui, T. Mayo Clin. Proc. 80(9):1220-1232 (2005).

The compounds, compositions and methods provided herein are also deemeduseful for the treatment of cancer. Cancers that may be treated by thecompounds, compositions and methods of the invention include, but arenot limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), colon, colorectal, rectal; Genitourinary tract:kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma,leukemia), bladder and urethra (squamous cell carcinoma, transitionalcell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma),testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma; unclassified carcinoma], granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acuteand chronic], acute lymphoblastic leukemia, chronic lymphocyticleukemia, myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignantlymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cellcarcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma; and Adrenal glands: neuroblastoma. Thus, the term“cancerous cell” as provided herein, includes a cell afflicted by anyone of the above-identified conditions.

The compounds, compositions and methods of the invention may also beuseful in treating the following disease states: keloids and psoriasis.

Cancers that may be treated by the compounds, compositions and methodsof the invention include, but are not limited to: breast, prostate,colon, colorectal, lung, brain, testicular, stomach, pancrease, skin,small intestine, large intestine, throat, head and neck, oral, bone,liver, bladder, kidney, thyroid and blood.

Cancers that may be treated by the compounds, compositions and methodsof the invention include: breast, prostate, colon, ovarian, colorectaland lung (non-small cell lung).

Cancers that may be treated by the compounds, compositions and methodsof the invention include: breast, colon, colorectal and lung.

Cancers that may be treated by the compounds, compositions and methodsof the invention include: lymphoma and leukemia.

The compounds of the instant invention are also inhibitors of theactivity of PDK1 and are thus useful in the treatment of cancer, inparticular cancers associated with deregulated activity of the PTEN/PI3Kpathway including, but not limited to PTEN loss of function mutationsand receptor tyrosine kinase gain of function mutations. Such cancersinclude, but are not limited to, ovarian, pancreatic, breast andprostate cancer, as well as cancers (including glioblastoma) where thetumor suppressor PTEN is mutated. See, Feldman, Richard I., et al.,“Novel Small Molecule Inhibitors of 3-Phosphoinositide-dependentKinase-1,” The Journal of Biological Chemistry, Vol. 280, No. 20, Issueof May 20, pp. 19867-19874, 2005.

PDK1 signaling regulates multiple critical steps in angiogenesis. See,Mora, Alfonso et al., “PDK1, the master regulator of AGC kinase signaltransduction,” Seminars in Cell & Developmental Biology 15 (2004)161-170. The utility of angiogenesis inhibitors in the treatment ofcancer is known in the literature, see J. Rak et al. Cancer Research,55:4575-4580, 1995 and Dredge et al., Expert Opin. Biol. Ther. (2002)2(8):953-966, for example. The role of angiogenesis in cancer has beenshown in numerous types of cancer and tissues: breast, carcinoma (G.Gasparini and A. L. Harris, J. Clin. Oncol., 1995, 13:765-782; M. Toi etal., Japan. J. Cancer Res., 1994, 85:1045-1049); bladder carcinomas (A.J. Dickinson et al., Br. J. Urol., 1994, 74:762-766); colon carcinomas(L. M. Ellis et al., Surgery, 1996, 120(5):871-878); and oral cavitytumors (J. K. Williams et al., Am. J. Surg., 1994, 168:373-380). Othercancers include, advanced tumors, hairy cell leukemia, melanoma,advanced head and neck, metastatic renal cell, non-Hodgkin's lymphoma,metastatic breast, breast adenocarcinoma, advanced melanoma, pancreatic,gastric, glioblastoma, lung, ovarian, non-small cell lung, prostate,small cell lung, renal cell carcinoma, various solid tumors, multiplemyeloma, metastatic prostate, malignant glioma, renal cancer, lymphoma,refractory metastatic disease, refractory multiple myeloma, cervicalcancer, Kaposi's sarcoma, recurrent anaplastic glioma, and metastaticcolon cancer (Dredge et al., Expert Opin. Biol Ther. (2002)2(8):953-966). Thus, the PDK1 inhibitors disclosed in the instantapplication are also useful in the treatment of these angiogenesisrelated cancers.

Tumors which have undergone neovascularization show an increasedpotential for metastasis. In fact, angiogenesis is essential for tumorgrowth and metastasis. (S. P. Cunningham, et al., Can. Research, 61:3206-3211 (2001)). The PDK1 inhibitors disclosed in the presentapplication are therefore also useful to prevent or decrease tumor cellmetastasis.

Further included within the scope of the invention is a method oftreating or preventing a disease in which angiogenesis is implicated,which is comprised of administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention. Ocular neovascular diseases are an example ofconditions where much of the resulting tissue damage can be attributedto aberrant infiltration of blood vessels in the eye (see WO 00/30651,published 2 Jun. 2000). The undesireable infiltration can be triggeredby ischemic retinopathy, such as that resulting from diabeticretinopathy, retinopathy of prematurity, retinal vein occlusions, etc.,or by degenerative diseases, such as the choroidal neovascularizationobserved in age-related macular degeneration. Inhibiting the growth ofblood vessels by administration of the present compounds would thereforeprevent the infiltration of blood vessels and prevent or treat diseaseswhere angio genesis is implicated, such as ocular diseases like retinalvascularization, diabetic retinopathy, age-related macular degeneration,and the like.

Further included within the scope of the invention is a method oftreating or preventing a non-malignant disease in which angiogenesis isimplicated, including but not limited to: ocular diseases (such as,retinal vascularization, diabetic retinopathy and age-related maculardegeneration), atherosclerosis, arthritis, psoriasis, obesity andAlzheimer's disease (Dredge et al., Expert Opin. Biol. Ther. (2002)2(8):953-966). In another embodiment, a method of treating or preventinga disease in which angiogenesis is implicated includes: ocular diseases(such as, retinal vascularization, diabetic retinopathy and age-relatedmacular degeneration), atherosclerosis, arthritis and psoriasis.

Further included within the scope of the invention is a method oftreating hyperproliferative disorders such as restenosis, inflammation,autoimmune diseases and allergy/asthma.

Further included within the scope of me instant invention is the use ofthe instant compounds to coat stents and therefore the use of theinstant compounds on coated stents for the treatment and/or preventionof restenosis (WO03/032809).

Further included within the scope of the instant invention is the use ofthe instant compounds for the treatment and/or prevention ofosteoarthritis (WO03/035048).

Further included within the scope of the invention is a method oftreating hypoinsulinism.

An embodiment of the invention provides a method for inhibiting JAK3tyrosine kinase, comprising administering to the mammal atherapeutically effective amount of any of the compounds or any of thepharmaceutical compositions described above.

An embodiment of the invention provides a method for inhibiting TYK2tyrosine kinase, comprising administering to the mammal atherapeutically effective amount of any of the compounds or any of thepharmaceutical compositions described above.

Exemplifying the invention is the use of any of the compounds describedabove in the preparation of a medicament for the treatment and/orprevention of osteoporosis in a mammal in need thereof. Still furtherexemplifying the invention is the use of any of the compounds describedabove in the preparation of a medicament for the treatment and/orprevention of: bone loss, bone resorption, bone fractures, metastaticbone disease and/or disorders related to cathepsin functioning.

The compounds of this invention may be administered to mammals,including humans, either alone or, in combination with pharmaceuticallyacceptable carriers, excipients or diluents, in a pharmaceuticalcomposition, according to standard pharmaceutical practice. Thecompounds can be administered orally or parenterally, including theintravenous, intramuscular, intraperitoneal, subcutaneous, rectal andtopical routes of administration.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, microcrystalline cellulose, sodiumcrosscarmellose, corn starch, or alginic acid; binding agents, forexample starch, gelatin, polyvinyl-pyrrolidone or acacia, andlubricating-agents, for example, magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to mask the unpleasant taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropylmethyl-cellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, cellulose acetate buryrate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable, emulsifying agents may benaturally-occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of sterile injectableaqueous solutions. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulation.

The injectable solutions or microemulsions may be introduced into apatient's blood-stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

Compounds of the instant invention may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter, glycerinatedgelatin, hydrogenated vegetable oils, mixtures of polyethylene glycolsof various molecular weights and fatty acid esters of polyethyleneglycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the instant invention are employed.(For purposes of this application, topical application shall includemouth washes and gargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles anddelivery devices, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in theart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen. Compounds of the presentinvention may also be delivered as a suppository employing bases such ascocoa butter, glycerinated gelatin, hydrogenated vegetable oils,mixtures of polyethylene glycols of various molecular weights and fattyacid esters of polyethylene glycol.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polyactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcrosslinked or amphipathic block copolymers of hydrogels.

When a composition according to this invention is administered into ahuman subject, the daily dosage will normally be determined by theprescribing physician with the dosage generally varying according to theage, weight, and response of the individual patient, as well as theseverity of the patient's symptoms.

In an embodiment, a suitable amount of an inhibitor of JAK2 isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount of inhibitor of between about 0.1 mg/kg of bodyweight to about 60 mg/kg of body weight per day, or between 0.5 mg/kg ofbody weight to about 40 mg/kg of body weight per day. Anothertherapeutic dosage that comprises the instant composition includes fromabout 0.01 mg to about 1000 mg of inhibitor of JAK2. In anotherembodiment, the dosage comprises from about 1 mg to about 1000mg ofinhibitor of JAK2.

The instant compounds are also useful in combination with therapeutic,chemotherapeutic and anti-cancer agents. Combinations of the presentlydisclosed compounds with therapeutic, chemotherapeutic and anti-canceragents are within the scope of the invention. Examples of such agentscan be found in Cancer Principles and Practice of Oncology by V. T.Devita and S. Hellman (editors), 6^(th) edition (Feb. 15, 2001),Lippincott Williams & Wilkins Publishers. A person of ordinary skill inthe art would be able to discern which combinations of agents would beuseful based on the particular characteristics of the drugs and thecancer involved. Such agents include the following: estrogen receptormodulators, androgen receptor modulators, retinoid receptor modulators,cytotoxic/cytostatic agents, antiproliferative agents, prenyl-proteintransferase inhibitors, HMG-CoA reductase inhibitors and otherangiogenesis inhibitors, HIV protease inhibitors, reverse transcriptaseinhibitors, inhibitors of cell proliferation and survival signaling,bisphosphonates, aromatase inhibitors, siRNA therapeutics, γ-secretaseinhibitors, agents that interfere with receptor tyrosine kinases (RTKs)and agents that interfere with cell cycle checkpoints. The instantcompounds are particularly useful when co-administered with radiationtherapy.

“Estrogen receptor modulators” refers to compounds that interfere withor inhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere orinhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide.

“Cytotoxic/cytostatic agents” refer to compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell myosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, histone deacetylase inhibitors,inhibitors of kinases involved in mitotic progression, inhibitors ofkinases involved in growth factor and cytokine signal transductionpathways, antimetabolites, biological response modifiers,hormonal/anti-hormonal therapeutic agents, haematopoietic growthfactors, monoclonal antibody targeted therapeutic agents, topoisomeraseinhibitors, proteosome inhibitors, ubiquitin ligase inhibitors, andaurora kinase inhibitors.

Examples of cytotoxic/cytostatic agents include, but are not limited to,sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin,altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine,nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine,improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride,pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum,benzylguanine, glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755,4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (seeWO 00/50032), Raf kinase inhibitors (such as Bay43-9006) and mTORinhibitors (such as Wyeth's CCI-779).

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteosome inhibitors include but are not limited tolactacystin and MLN-341 (Velcade).

Examples of microtubule inhibitors/microtubule-stabilising agentsinclude paclitaxel, vindesine sulfate,3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol, rhizoxin,dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881,BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS188797. In an embodiment the epothilones are notincluded in the microtubule inhibitors/microtubule-stabilising agents.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-k1]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine, (5a, 5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydro0xy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoguinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one, and dimesna.

Examples of inhibitors of mitotic kinesins, and in particular the humanmitotic kinesin KSP, are described in Publications WO03/039460,WO03/050064, WO03/050122, WO03/049527, WO03/049679, WO03/049678,WO04/039774, WO03/079973, WO03/099211, WO03/105855, WO03/106417,WO04/037171, WO04/058148, WO04/058700, WO04/126699, WO05/018638,WO05/019206, WO05/019205, WO05/018547, WO05/017190, US2005/0176776. Inan embodiment inhibitors of mitotic kinesins include, but are notlimited to inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E,inhibitors of MCAK and inhibitors of Rab6-KIFL.

Examples of “histone deacetylase inhibitors” include, but are notlimited to, SAHA, TSA, oxamflatin, PXD101, MG98 and scriptaid. Furtherreference to other histone deacetylase inhibitors may be found in thefollowing manuscript; Miller, T. A. et al. J. Med. Chem.46(24):5097-5116 (2003).

“Inhibitors of kinases involved in mitotic progression” include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub-1and inhibitors of bub-R1. An example of an “aurora kinase inhibitor” isVX-680.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine, N-[5 -(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-flurouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine,3-aminopyridine-2-carboxaldehyde thiosemicarbazone and trastuzumab.

Examples of monoclonal antibody targeted therapeutic agents includethose therapeutic agents which have cytotoxic agents or radioisotopesattached to a cancer cell specific or target cell specific monoclonalantibody. Examples include Bexxar.

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductaseinhibitors that may be used include but are not limited to lovastatin(MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039),simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850and4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227,4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®;see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164,5,118,853, 5,290,946 and 5,356,896), atorvastatin (LIPITOR®; see U.S.Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952) andcerivastatin (also known as rivastatin and BAYCHOL®; see U.S. Pat. No.5,177,080). The structural formulas of these and additional HMG-CoAreductase inhibitors that may be used in the instant methods aredescribed at page 87 of M. Yalpani, “Cholesterol Lowering Drugs”,Chemistry & Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos.4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as usedherein includes all pharmaceutically acceptable lactone and open-acidforms (i.e., where the lactone ring is opened to form the free acid) aswell as salt and ester forms of compounds which have HMG-CoA reductaseinhibitory activity, and therefor the use of such salts, esters,open-acid and lactone forms is included within the scope of thisinvention.

“Prenyl-protein transferase inhibitor” refers to a compound whichinhibits any one or any combination of the prenyl-protein transferaseenzymes, including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase).

Examples of prenyl-protein transferase inhibitors can be found in thefollowing publications and patents: WO 96/30343, WO 97/18813, WO97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO95/32987, U.S. Pat. Nos. 5,420,245, 5,523,430, 5,532,359, 5,510,510,5,589,485, 5,602,098, European Patent Publ. 0 618 221, European PatentPubl. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ:0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of aprenyl-protein transferase inhibitor on angiogenesis see European J. ofCancer, Vol. 35, No. 9, pp. 1394-1401 (1999).

“Angiogenesis inhibitors” refers to compounds that inhibit the formationof new blood vessels, regardless of mechanism. Examples of angiogenesisinhibitors include, but are not limited to, tyrosine kinase inhibitors,such as inhibitors of the tyrosine kinase receptors Flt-1(VEGFR1) andFlk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived,or platelet derived growth factors, MMP (matrix metalloprotease)inhibitors, integrin blockers, interferon-α, interleukin-12, pentosanpolysulfate, cyclooxygenase inhibitors, including nonsteroidalanti-inflammatories (NSAIDs) like aspirin and ibuprofen as well asselective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib(PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch.Opthalmol., Vol. 108, p. 573 (1990); Anat. Rec., Vol. 238, p. 68 (1994);FEBS Letters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76(1995); J. Mol. Endocrinol., Vol. 16, p. 107. (1996); Jpn. J.Pharmacol., Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625(1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715(1998); J. Biol. Chem., Vol. 274, p. 911.6 (1999)), steroidalanti-inflammatories (such as corticosteroids, mineralocorticoids,dexamethasone, prednisone, prednisolone, methylpred, betamethasone),carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab.Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see, NatureBiotechnology, Vol. 17, pp.963-968 (October 1999); Kim et al., Nature,362, 841-844 (1993); WO 00/44777; and WO 00/61186).

Other therapeutic agents that modulate or inhibit angiogenesis and mayalso be used in combination with the compounds of the instant inventioninclude agents that modulate or inhibit the coagulation and fibrinolysissystems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examplesof such agents that modulate or inhibit the coagulation and fibrinolysispathways include, but are not limited to, heparin (see Thromb. Haemost.80:10-23 (1998)), low molecular weight heparins and carboxypeptidase Uinhibitors (also known as inhibitors of active thrombin activatablefibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101:329-354(2001)). TAFIa inhibitors have been described in U.S. Ser. Nos.60/310,927 (filed Aug. 8, 2001) and 60/349,925 (filed Jan. 18, 2002).

“Agents that interfere with cell cycle checkpoints” refer to compoundsthat inhibit protein kinases that transduce cell cycle checkpointsignals, thereby sensitizing the cancer cell to DNA damaging agents.Such agents include inhibitors of ATR, ATM, the CHK11 and CHK12 kinasesand cdk and cdc kinase inhibitors and are specifically exemplified by7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

“Agents that interfere with receptor tyrosine kinases (RTKs)” refer tocompounds that inhibit RTKs and therefore mechanisms involved inoncogenesis and tumor progression. Such agents include inhibitors ofc-Kit, Eph, PDGF, Flt3 and c-Met. Further agents include inhibitors ofRTKs as described by Bume-Jensen and Hunter, Nature, 411:355-365, 2001.

“Inhibitors of cell proliferation and survival signalling pathway” referto compounds that inhibit signal transduction cascades downstream ofcell surface receptors. Such agents include inhibitors ofserine/threonine kinases (including but not limited to inhibitors of Aktsuch as described in WO 02/083064, WO 02/083139, WO 02/083140, US2004-0116432, WO 02/083138, US 2004-0102360, WO 03/086404, WO 03/086279,WO 03/086394, WO 03/084473, WO 03/086403, WO 2004/041162, WO2004/096131, WO 2004/096129, WO 2004/096135, WO 2004/096130, WO2005/100356, WO 2005/100344, US 2005/029941, US 2005/44294, US2005/43361, U.S. Ser. Nos. 60/734188, 60/652737, 60/670469), inhibitorsof Raf kinase (for example BAY-43-9006 ), inhibitors of MEK (for exampleCI-1040 and PD-098059), inhibitors of mTOR (for example Wyeth CCI-779),and inhibitors of PI3K (for example LY294002).

As described above, the combinations with NSAID's are directed to theuse of NSAID's which are potent COX-2 inhibiting agents. For purposes ofthis specification an NSAID is potent if it possesses an IC₅₀ for theinhibition of COX-2 of 1 μM or less as measured by cell or microsomalassays.

The invention also encompasses combinations with NSAID's which areselective COX-2 inhibitors. For purposes of this specification NSAID'swhich are selective inhibitors of COX-2 are defined as those whichpossess a specificity for inhibiting COX-2 over COX-1 of at least 100fold as measured by the ratio of IC₅₀ for COX-2 over IC₅₀ for COX-1evaluated by cell or microsomal assays. Such compounds include, but arenot limited to those disclosed in U.S. Pat. Nos. 5,474,995, 5,861,419,6,001,843, 6,020,343, 5,409,944, 5,436,265, 5,536,752, 5,550,142,5,604,260, 5,698,584, 5,710,140, WO 94/15932, U.S. Pat. Nos. 5,344,991,5,134,142, 5,380,738, 5,393,790, 5,466,823, 5,633,272 and 5,932,598, allof which are hereby incorporated by reference.

Inhibitors of COX-2 that are particularly useful in the instant methodof treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;and5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; ora pharmaceutically acceptable salt thereof.

Compounds that have been described as specific inhibitors of COX-2 andare therefore useful in the present invention include, but are notlimited to, the following: parecoxib, BEXTRA® and CELEBREX® or apharmaceutically acceptable salt thereof.

Other examples of angiogenesis inhibitors include, but are not limitedto, endostatin, ukrain, ranpirnase, IM862,5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101,squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaosephosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

As used above, “integrin blockers” refers to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe α_(v)β₃ integrin, to compounds which selectively antagonize, inhibitor counteract binding of a physiological ligand to the αvβ5 integrin, tocompounds which antagonize, inhibit or counteract binding of aphysiological ligand to both the α_(v)β₃ integrin and the α_(v)β₅integrin, and to compounds which antagonize, inhibit or counteract theactivity of the particular integrin(s) expressed on capillaryendothelial cells. The term also refers to antagonists of the α_(v)β₆,α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The term also refersto antagonists of any combination of α_(v)β₃, α_(v)β₅, α_(v)β₆, α_(v)β₈,α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins.

Some specific examples of tyrosine kinase inhibitors includeN-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,17-(allylamino)-17-demethoxygeldanamycin,4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline,N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,BIBX1382,2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one,SH268, genistein, STI571, CEP2563,4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A,N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.

Combinations with compounds other than anti-cancer compounds are alsoencompassed in the instant methods. For example, combinations of theinstantly claimed compounds with PPAR-γ (i.e., PPAR-gamma) agonists andPPAR-δ (i.e., PPAR-delta) agonists are useful in the treatment ofcertain malingnancies. PPAR-γ and PPAR-δ are the nuclear peroxisomeproliferator-activated receptors γ and δ. The expression of PPAR-γ onendothelial cells and its involvement in angiogenesis has been reportedin the literature (see J. Cardiovasc. Pharmacol. 1998; 31:909-913; J.Biol. Chem. 1999,274:9116-9121; Invest. Ophthalmol Vis. Sci. 2000;41:2309-2317). More recently, PPAR-γ agonists have been shown to inhibitthe angiogenic response to VEGF in vitro; both troglitazone androsiglitazone maleate inhibit the development of retinalneovascularization in mice. (Arch. Ophthamol. 2001; 119:709-717).Examples of PPAR-γ agonists and PPAR-γ/α agonists include, but are notlimited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone,rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate,GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544,NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926,2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionicacid (disclosed in U.S. Ser. No. 09/782,856), and2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid (disclosed in U.S.Ser. No. 60/235,708 and 60/244,697).

Another embodiment of the instant invention is the use of the presentlydisclosed compounds in combination with gene therapy for the treatmentof cancer. For an overview of genetic strategies to treating cancer seeHall et al (Am. J. Hum. Genet. 61:785-789, 1997) and Kufe et al (CancerMedicine, 5th Ed, pp 876-889, B C Decker, Hamilton 2000). Gene therapycan be used to deliver any tumor suppressing gene. Examples of suchgenes include, but are not limited to, p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example), a uPA/uPAR antagonist (“Adenovirus-Mediated Delivery of auPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth andDissemination in Mice,” Gene Therapy, August 1998;5(8):1105-13), andinterferon gamma (J. Immunol. 2000;164:217-222).

The compounds of the instant invention may also be administered incombination with an inhibitor of inherent multidrug resistance (MDR), inparticular MDR associated with high levels of expression of transporterproteins. Such MDR inhibitors include inhibitors of p-glycoprotein(P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833(valspodar).

A compound of the present invention may be employed in conjunction withanti-emetic agents to treat nausea or emesis, including acute, delayed,late-phase, and anticipatory emesis, which may result from the use of acompound of the present invention, alone or with radiation therapy. Forthe prevention or treatment of emesis, a compound of the presentinvention may be used in conjunction with other anti-emetic agents,especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists,such as ondansetron, granisetron, tropisetron, and zatisetron, GABABreceptor agonists, such as baclofen, a corticosteroid such as Decadron(dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten orothers such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401,3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, anantidopaminergic, such as the phenothiazines (for exampleprochlorperazine, fluphenazine, thioridazine and mesoridazine),metoclopramide or dronabinol. In another embodiment, conjunctive therapywith an anti-emesis agent selected from a neurokinin-1 receptorantagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosedfor the treatment or prevention of emesis that may result uponadministration of the instant compounds.

Neurokinin-1 receptor antagonists of use in conjunction with thecompounds of the present invention are fully described, for example, inU.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595,5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European PatentPublication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0545 478, 0 558 156, 0 577 394, 0 585 913,0 590 152, 0 599 538, 0 610793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959,0 733 632and 0 776 893; PCT International Patent Publication Nos. WO 90/05525,90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585,92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330, 93/00331,93/01159, 93/01165, 93/01169, 93/01170, 93/06099,93/09116, 93/10073,93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181,93/23380,93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429,94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165,94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767,94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309,95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549,95/11880, 95/14017,95/15311, 95/16679, 95/17382, 95/18124, 95/18129,95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418,95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094,96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304,96/29317,96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553,97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084,97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529,2 268 931, 2 269 170, 2,269 590, 2 271 774 74, 2 292 144, 2 293 168, 2293 169, and 2 302 689. The preparation of such compounds is fullydescribed in the aforementioned patents and publications, which areincorporated herein by reference.

In an embodiment, the neurokinin-1 receptor antagonist for use inconjunction with the compounds of the present invention is selectedfrom:2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine,or a pharmaceutically acceptable salt thereof, which is described inU.S. Pat. No. 5,719,147.

A compound of the instant invention may also be administered with anagent useful in the treatment of anemia. Such an anemia treatment agentis, for example, a continuous eythropoiesis receptor activator (such asepoetin alfa).

A compound of the instant invention may also be administered with anagent useful in the treatment of neutropenia. Such a neutropeniatreatment agent is, for example, a hematopoietic growth factor whichregulates the production and function of neutrophils such as a humangranulocyte colony stimulating factor, (G-CSF). Examples of a G-CSFinclude filgrastim.

A compound of the instant invention may also be administered with animmunologic-enhancing drug, such as levamisole, isoprinosine andZadaxin.

A compound of the instant invention may also be useful for treating orpreventing cancer, including bone cancer, in combination withbisphosphonates (understood to include bisphosphonates, diphosphonates,bisphosphonic acids and diphosphonic acids). Examples of bisphosphonatesinclude but are not limited to: etidronate (Didronel), pamidronate(Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate(Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate,EB-1053, minodronate, neridronate, piridronate and tiludronate includingany and all pharmaceutically acceptable salts, derivatives, hydrates andmixtures thereof.

A compound of the instant invention may also be useful for treating orpreventing breast cancer in combination with aromatase inhibitors.Examples of aromatase inhibitors include but are not limited to:anastrozole, letrozole and exemestane.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with siRNA therapeutics.

The compounds of the instant invention may also be administered incombination with γ-secretase inhibitors and/or inhibitors of NOTCHsignaling. Such inhibitors include compounds described in WO 01/90084,WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO03/093264, WO 03/093251, WO 03/093253, WO 2004/039800, WO 2004/039370,WO 2005/030731, WO 2005/014553, U.S. Ser. No. 10/957,251, WO2004/089911, WO 02/081435, WO 02/081433, WO 03/018543, WO 2004/031137,WO 2004/031139, WO 2004/031138, WO 2004/101538, WO 2004/101539 and WO02/47671 (including LY-450139).

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with inhibitors of Akt. Such inhibitorsinclude compounds described in, but not limited to, the followingpublications: WO 02/083064, WO 02/083139, WO 02/083140, US 2004-0116432,WO 02/083138, US 2004-0102360, WO 03/086404, WO 03/086279, WO 03/086394,WO 03/084473, WO 03/086403, WO 2004/041162, WO 2004/096131, WO2004/096129, WO 2004/096135, WO 2004/096130, WO 2005/100356, WO2005/100344, US 2005/029941, US 2005/44294, US 2005/43361, 60/734188,60/652737, 60/670469.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with PARP inhibitors.

A compound of the instant invention may also be useful for treatingcancer in combination with the following therapeutic agents: abarelix(Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®);Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol(Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole(Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®);azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules(Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®);bortezomib (Velcade®); busulfan intravenous (Busulfex®); busulfan oral(Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®);carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine(Gliadel®); carmustine with Polifeprosan 20Implant (Gliadel Wafer®);celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®);cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine(Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide(Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine(Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®);dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®);daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin(Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); Denileukindiftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®);doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®);doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®);dromostanolone propionate (Dromostanolone®); dromostanolone propionate(Masterone Injection®); Elliott's B Solution (Elliott's B Solution®);epirubicin (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®);estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide,VP-16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®);floxuridine (intraarterial) (FUDR®); fludarabine (Fludara®);fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib(Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®);goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®);histrelin acetate (Histrelin implant®); hydroxyurea (Hydrea®);Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide(IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®);Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide(Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®,Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®);lomustine, CCNU (CeeBU®); meclorethamine, nitrogen mustard (Mustargen®);megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®);mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnextabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C(Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®);nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®);Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®);paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-boundparticles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®);pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®);Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin(Nipent®); pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®);porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine(Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim(Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin(Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen(Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®);testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa(Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab(Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab(Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (UracilMustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®);vincristine (Oncovin®); vinorelbine (Navelbine®); and zoledronate(Zometa®).

Thus, the scope of the instant invention encompasses the use of theinstantly claimed compounds in combination with a second compoundselected from: an estrogen receptor modulator, an androgen receptormodulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent,an antiproliferative agent, a prenyl-protein transferase inhibitor, anHMG-CoA reductase inhibitor, an HIV protease inhibitor, a reversetranscriptase inhibitor, an angiogenesis inhibitor, PPAR-γ agonists,PPAR-δ agonists, an inhibitor of inherent multidrug resistance, ananti-emetic agent, an agent useful in the treatment of anemia, an agentuseful in the treatment of neutropenia, an immunologic-enhancing drug,an inhibitor of cell proliferation and survival signaling, abisphosphonate, an aromatase inhibitor, an siRNA therapeutic,γ-secretase inhibitors, agents that interfere with receptor tyrosinekinases (RTKs), an agent that interferes with a cell cycle checkpointand any of the therapeutic agents listed above.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, but also to an effect that results in theinhibition of growth and/or metastasis of the cancer.

Also included in the scope of the claims is a method of treating cancerthat comprises administering a therapeutically effective amount of acompound of the instant invention in combination with radiation therapyand/or in combination with a second compound selected from: an estrogenreceptor modulator, an androgen receptor modulator, a retinoid receptormodulator, a cytotoxiccytostatic agent, an antiproliferative agent, aprenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, anHIV protease inhibitor, a reverse transcriptase inhibitor, anangiogenesis inhibitor, PPAR-γ agonists, PPAR-δ agonists, an inhibitorof inherent multidrug resistance, an anti-emetic agent, an agent usefulin the treatment of anemia, an agent useful in the treatment ofneutropenia, an immunologic-enhancing drug, an inhibitor of cellproliferation and survival signaling, a bisphosphonate, an aromataseinhibitor, an siRNA therapeutic, γ-secretase inhibitors, agents thatinterfere with receptor tyrosine kinases (RTKs), an agent thatinterferes with a cell cycle checkpoint and any of the therapeuticagents listed above.

The instant invention also includes a pharmaceutical composition usefulfor treating or preventing cancer that comprises a therapeuticallyeffective amount of a compound of the instant invention and a secondcompound selected from: an estrogen receptor modulator, an androgenreceptor modulator, a retinoid receptor modulator, acytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-proteintransferase inhibitor, an HMG-CoA reductase inhibitor, an HIV proteaseinhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor,a PPAR-γ agonist, a PPAR-δ agonist, an inhibitor of cell proliferationand survival signaling, a bisphosphonate, an aromatase inhibitor, ansiRNA therapeutic, γ-secretase inhibitors, agents that interfere withreceptor tyrosine kinases (RTKs), an agent that interferes with a cellcycle checkpoint and any of the therapeutic agents listed above.

All patents, publications and pending patent applications identified arehereby incorporated by reference.

Abbreviations used in the description of the chemistry and in theExamples that follow are:

CH₂Cl₂ methylene chloride DCM dichloromethane DMSO dimethyl sulfoxideEtOAc ethyl acetate HCl hydrochloric acid HPLC high-performance liquidchromatography HRMS high resolution mass spectrum LRMS low resolutionmass spectrum MgSO₄ magnesium sulfate NaHCO₃ sodium bicarbonate NaOHsodium hydroxide Na₂SO₄ sodium sulfate NMR (nuclear magnetic resonance);Pd₂(dba)₃ tris(dibenzylideneacetone) dipalladium(0) SEMCl2-(trimethylsilyl)ethoxymethyl chloride TBAF tetrabutylanunoniumfluoride THF tetrahydrofuran TiCl₃ titanium chloride

The compounds of the present invention can be prepared according to thefollowing general schemes, using appropriate materials, and are furtherexemplified by the subsequent specific examples. The compoundsillustrated in the examples are not, however, to be construed as formingthe only genus that is considered as the invention. The illustrativeExamples below, therefore, are not limited by the compounds listed or byany particular substituents employed for illustrative purposes. Thoseskilled in the art will readily understand that known variations of theconditions and processes of the following preparative procedures can beused to prepare these compounds. All temperatures are degrees Celsiusunless otherwise noted.

General procedures to prepare compounds of the instant invention aredescribed in Scheme A. Treatment of 2-fluoro-4-methylpyridine with abase, such as NaHMDS, followed by the addition alkylbenzoate II providesketone III. Ketone III can be oxidized to oxime IV by the action of analkyl nitrite. Condensation of IV with an aldehyde (V) and ammoniumacetate, by either heating in a conventional manner or in a microwave,leads to imidazoles of structure VI. The hydroxyimidazole can be reducedusing a variety of different reducing agents, such as TiCl₃, to furnishVII. Subjection of a solution of VII to a source of high intensityphotochemical radiation leads to compounds of the instant invention asembodied by VIII.

General procedures to prepare compounds of the instant invention arealso described in Scheme B. Treatment of bromide VIII with a source ofpalladium, an amine, and an organic or inorganic base will furnishcompounds of the instant invention as embodied by structure IX.

General procedures to prepare compounds of the instant invention arealso described in Scheme C. Treatment of bromide VIII with a source ofpalladium, Mo(CO)₆, and an organic or inorganic base, will furnishcompounds of the instant invention as embodied by structure X.

General procedures to prepare compounds of the instant invention arealso described in Scheme D. Those skilled in the art synthetic organicchemistry could choose from a suitable list of protecting groups toallow for the preparation of compounds of the instant invention asembodied by sulfonyl-urea XIII in Scheme D. As an example, treatment ofcompound VIII with a base, such as NaH or tBuOK followed by SEM-Cl, willfurnish the bis-SEM material XI. Treatment of bromide XI with a sourceof palladium, a sulfonyl-urea, and an organic or inorganic base willfurnish XII. Removal of the SEM protecting groups under the action of afluoride source such TBAF, ZnF, or CsF or under acidic treatment such asHCl with or without conventional heating or with a microwave, willprovide compounds of the instant invention as embodied by XIII.

General procedures to prepare compounds of the instant invention arealso described in Scheme E. Treatment of bromide VIII with a source ofpalladium, an alkyl-, aryl-, or heteroarylboronic acid, and an inorganicbase furnishes compounds of the instant invention as embodied bystructure XIV.

General procedures to prepare compounds of the instant invention arealso described in Scheme F. Treatment of bromide VIII with a source ofpalladium, an alkyl-, aryl-, or heteroarylboronate ester, and aninorganic base furnished the instant invention as embodied by structureXIV.

General procedures to prepare compounds of the instant invention arealso described in Scheme G. Treatment of bromide VIII with a source ofpalladium, bis-pinacolborane, and an inorganic base furnishes boronateXV. Treatment of boronate XV with a source of palladium, an aryl- orheteroaryl-halide, R₂X, where X is chosen from chloride, bromide, oriodide, or aryl- or heteroaryl-triflate, R₂X, and an inorganic basefurnishes compounds of the instant invention as embodied by structureXIV.

The compounds of this invention may be prepared by employing reactionsas shown in the following Examples, in addition to other standardmanipulations that are known in the literature or exemplified in theexperimental procedures.

EXAMPLE 1

9-Bromo-2-(2-Chloro-6-Fluorophenyl)-3,6-Dihydro-7H-Benzo[H]Imidazo[4,5-F]Isoquinolin-7-One

Step A: 1-(4-bromophenyl)-2-(2-fluoropyridin-4-yl)ethanone

To a solution of sodium bis(trimethylsilyl)amide (235 mL, 2M) in THF(750 mL) under nitrogen, cooled to 2° C., was added2-fluoro-4-methylpyridine (25 g, 0.225 mol) and the solution stirred for45 minutes in an ice bath. Ethyl 4-bromobenzoate (55 g, 0.239 mol) wasadded and the reaction was stirred overnight at RT. The reaction mixturewas poured into excess aqueous 2N HCl, and the aqueous layer was madebasic with 5 N NaOH and extracted with EtOAc. The organic extracts werecombined, washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was dissolved in CH₂Cl₂ and filteredthrough a cotton plug. Hexanes were added and the CH₂Cl₂ was removedunder reduced pressure until precipitation of the title compoundoccurred as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃): δ8.20 (m, 1H),7.85 (m, 2H), 7.65 (m, 2H), 7.05 (m, 1H), 6.82 (m, 1H), 4.30(s, 2H).

Step B: 1 -(4-bromophenyl)-2-(2-fluoropyridin-4-yl)ethane-1,2-dione2-oxime

To a solution of the intermediate from Example 1 Step A (48 g, 0.163mol) in ethanol (800 mL) at −10° C. was added dropwise t-butylnitrite(22.1 mL, 0.18 mol) over 10 minutes, followed by 2.5 N HCl in absoluteethanol (52 mL, 0.13 mol). The reaction temperature was maintained at−5° C. during these additions. After the addition was completed, the dryice bath was removed and the reaction was allowed to warm to RTovernight. The ethanol was removed under reduced pressure and theresidue was diluted with H₂O. The aqueous phase was made basic withsaturated NaHCO₃ and extracted with EtOAc. The combined organic extractswere washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure. The crude residue was taken up in methanol/isopropanol andmixed with toluene. The methanol/isopropanol mixture was concentratedunder reduced pressure and the title compound was recrystallized fromhexane/toluene. ¹H NMR (400 MHz, CDCl₃): δ8.22 (m, 1H), 7.78 (m, 2H),7.65 (m, 2H), 7.32 (m, 1H), 7.08(s, 1H).

Step C:4-[4-(4-bromophenyl)-2-(2-chloro-6-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

To a solution of the intermediate from Example 1 Step 3 (14 g, 0.04 mol)in acetic acid (500 mL) and under nitrogen was added2-chloro-6-fluorobenzaldehyde (7.9 g, 0.05 mol) and ammonium acetate (62g, 0.8 mol). The reaction solution was heated to reflux overnight. Theacetic acid was removed under reduced pressure and the remainingmaterial was taken up in water. The pH of the solution was adjusted to8-10 by the addition of solid ammonium hydroxide and then extractedseveral time with EtOAc. The solvent was removed under reduced pressureand the crude product was dissolved in ethanol twice and concentrated toa small volume under reduced pressure to azeotropically remove water.The title compound was recrystallized from ethanol and hexane. ¹H NMR(400 MHz, DMSO-d₆): δ11.95 (br, 2H), 7.35˜7.70 (m, 8H), 6.45 (m, 1H),6.15 (m, 1H).

Step D:4-[4-(4-bromophenyl)-2-(2-chloro-6-fluorophenyl)-1H-imidazol-5-yl]pyridin-2(1H)-one

To a solution of the intermediate from Example 1 Step C (11 g, 0.024mol) in methanol (0.5 L) at 0° C. under nitrogen was added TiCl₃(15˜20%, 120 mL) over 45 minutes while maintaining the reactiontemperature under 10° C. The solution was warmed to RT and stirredovernight. The volatiles were removed under reduced pressure, and thesolution was made basic with saturated NaHCO₃ and 5 N NaOH. Ethylacetate was added and the mixture was stirred overnight. The solutionwas filtered through a Solka floe pad to remove the solids. The filtratewas extracted with EtOAc and the organic layer was then washed twicewith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to provide the crude residue which was purified by on silicagel (gradient elution with 2%-10% DCM-methanol as an eluant) to yieldthe title compound. ¹H NMR (300 MHz, DMSO-d6): δ13.12 (m, 1H), 11.45(br, 1H), 7.22˜7.70 (m, 9H), 6.10˜6.32 (m, 2H).

Step E:9-bromo-2-(2-chloro-6-fluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

The intermediate from Example 1 Step D (2.9 g, 6.55 mmol) was dissolvedin 200 mL of a 60:40 mixture of 1,2-dichloroethane-ethanol. The mixturewas irradiated under a high intensity light for 3 days. The volatileswere removed in vacuo and the crude material was triturated with DCM andfiltered. The product was triturated twice more with EtOAc and filtered.¹ NMR 400 MHz, DMSO-d₆: δ14.12 (br, 1H), 11.82 (m, 1H), 10.55(m, 1H),7.40˜7.90(m, 7H): [M+1]⁺ 442.

EXAMPLE 2

9-Bromo-2-Cyclopentyl-3,6-Dihydro-7H-Benzo[H]Imidazo[4,5-F)]Isoquinolin-7-One

Step A:4-[4-(4-bromophenyl)-2-cyclopentyl-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

Using the general procedure found in Example 1 Step C, the intermediatefrom Example 1 Step B was combined with cyclopentane carboxaldehyde andammonium acetate and acetic acid. ¹H NMR (400 MHz, DMSO-d₆): δ11.95 (br,2H), 7.35˜7.70 (m, 8H), 6.45 (m, 1H), 6.15 (m, 1H).

Step B:4-[4-(4-bromophenyl)-2-cyclopentyl-1H-imidazol-5-yl]pyridin-2(1H)-one

Using the general procedure in Example 1 Step D, the intermediate ofExample 2 Step A was treated with TiCl₃ in methanol. ¹H NMR (400 MHz,DMSO-d₆): δ 12.22 (m, 1H), 11.30 (br, H), 7.20˜7.65 (m, 5H), 6.0˜6.39(m, 2H), 3.08 (m, 1H), 1.5˜1.85 (m,8H).

Step C:9-bromo-2-cyclopentyl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

Using the general procedure in Example 1 Step E, the intermediate ofExample 2 Step B was was irradiated under a high intensity light in THF.¹H NMR (600 MHz, DMSO) δ: 13.18 (s, 1 H), 13.05 (s, 1 H)*, 11.72 (d,J=5.6 Hz, 1 H)*, 11.66 (d, J=5.6 Hz, 1 H), 10.52 (d, J=2.0 Hz , 1 H),10.44 (d, J=2.0 Hz, 1 H)*, 8.43 (d, J=8.8 Hz, 1 H)*, 8.32 (d, J=8.5 Hz,1 H), 7.82 (dd, J=8.5, 2.0, 1 H), 7.74 (dd, J=8.8, 2.0 Hz, 1 H)*, 7.61(m, 1 H)*, 7.52 (m, 1 H), 7.24 (dd, J=6.8, 1.5 Hz, 1 H), 7.14 (dd,J=6.8, 1.5 Hz, 1 H)*, 2.13 (m, 2 H), 2.13 (m, 2 H)*, 1.98 (m, 2 H), 1.98(m, 2 H)*, 1.82 (m, 2 H), 1.82 (m, 2 H)*, 1.69 (m, 2 H), 1.69 (m, 2 H)*(note: *—denotes peaks derived from the minor tautomer): [M+1]⁺ 382.

EXAMPLE 3

9-Bromo-2-(2-Chlorophenyl)-3,6-Dihydro-7H-Benzo[H]Imidazo[4,5-F]Isoquinolin-7-One

Step A:4-[4-(4-bromophenyl)-2-(2-chlorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

Using the general procedure found in Example 1 Step C, the intermediatefrom Example 1 Step B was combined with 2-chlorobenzaldehyde, ammoniumacetate and acetic acid.

Step B:4-[4-(4-bromophenyl)-2-(2-chlorophenyl)-1H-imidazol-5-yl]pyridin-2(1H)-one

Using the general procedure in Example 1 Step D, the intermediate ofExample 3 Step A was treated with TiCl₃ in methanol. ¹H NMR (400 MHz,DMSO-d₆): [M+1]⁺ 427.

Step C:9-bromo-2-(2-chlorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

Using the general procedure in Example 1 Step E, the intermediate ofExample 3 Step B was was irradiated under a high intensity light in THF.¹H NMR (600 MHz, DMSO) δ: 13.87 (s, 1 H), 13.76 (s, 1 H)*, 11.86 (m, 1H)*,11.77 (m, 1 H), 10.55 (d, J=2.0 Hz, 1 H), 10.49 (d, J=2.0 Hz, 1 H)*,8.49 (d, J=8.5 Hz, 1 H), 8.41 (d, J=8.5 Hz, 1 H)*, 7.88 (m, 1 H), 7.88(m, 1 H)*, 7.86 (m, 1 H), 7.81 (m, 1 H)*, 7.70 (m, 1 H), 7.70 (m, 1 H)*,7.57 (m, 3 H), 7.57 (m, 3H)*, 7.31 (m, 1 H), 7.24 (m, 1 H)* (note: *denotes peaks derived from the minor tautomer): [M+1]⁺ 424.

EXAMPLE 4

2-Cyclopentyl-9-(Isobutylamino)-3,6-Dihydro-7H-Benzo[H]Imidazo[4,5-F]Isoquinolin-7-OneStep A:2-cyclopentyl-10-(isobutylamino)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

A 0.5-2 mL microwave vial containing a stir bar was placed under argonby attaching a rubber septum and performing 4 vacuum/argon cycles. Thearyl bromide from Example 2, Step C, (41.8 mg, 0.065 mmol), sodiumtert-butoxide (9.4 mg, 0.0975 mmol), 2-(di-tert-butylphosphino)biphenyl(3.9 mg, 0.013 mmol), Pd₂(dba)₃ (6.0 mg, 0.0065 mmol) were added, andthe vial was sealed. While adding the solids to the vial, 30 mL oftoluene was deoxygenated by bubbling argon through for 30 minutes; 0.4mL of this was added to the sealed reaction vial. Isobutyl amine (0.009ml, 0.094 mmol) was added via microsyringe, and then argon was flushedgently through the vial for 5 min. The reaction was heated to 100° C.for 24hours and then cooled to room temperature. A solution oftetrabutylammonium fluoride (1 M in tetrahydrofuran, 0.20 ml, 0.02 mmol)was added, and the vial was heated in a microwave oven for 5 min at 150°C. for 5 min at 170° C. After cooling to room temperature, the reactionmixture was partitioned between a 1:1 mixture of EtOAc:ether (4 mL) and1:1 water:saturated NaHCO₃ (3 mL). The layers were separated, and theorganic layer was washed with brine (3 mL), dried over MgSO4, filtered,and concentrated. The resulting solid was purified by reverse phaseHPLC. After lypophilization, the title compound was obtained: [M+1]⁺375.

EXAMPLE 5

2-Cyclopentyl-N-[2-(Dimethylamino)ethyl]-7-Oxo-6,7-Dihydro-3H-Benzo[H]Imidazo[4,5-F]Isoquinoline-9-CarboxamideStep A:2-cyclopentyl-N-[2-(dimethylamino)ethyl]-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinoline-9-carboxamide

A 0.5-2 mL microwave vial was charged with a stir bar, aryl bromide fromExample 2, Step C; (50 mg, 0.131 mmol), molybdenum hexacarbonyl (34.6mg, 0.131 mmol), tri-tert-butylphosphine tetrafluoroborate (3.8 mg,0.013) mmol), andtrans-di(mu-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II)(6.1 mg, 0.0066 mmol). A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene(0.06 mL, 0.524 mmol) and N,N-dimethylethylenediamine (0.054 mL, 0.393mmol) in 1,4-dioxane (0.65 mL) was added to the vial, and the vial wassealed. The reaction was then heated in a microwave oven for 15 min at140° C. After cooling to room temperature, the reaction mixture wastransferred to a scintillation vial using methanol and concentrated todryness. The crude product was purified by reverse phase HPLC whichprovided the title compound. ¹ H NMR (600 MHz, DMSO) δ: 13.19 (s, 1 H),13.04 (s, 1 H)*, 11.68 (s, 1H)*, 11.60 (s, 1 H), 10.70 (s ,1 H), 10.64(s, 1 H)*, 8.50 (s, 1 H)*, 8.38 (m, 2 H), 8.36 (m, 1 H)*, 8.24 (s, 1 H),8.24 (s, 1 H)*, 8.00 (s, 1 H)*, 7.98 (s, 1 H), 7.58 (s, 1 H)*, 7.50 (s,1 H), 7.22 (s, 1 H), 7.14 (s, 1 H)*, 3.42 (m, 4 H), 3.42 (m, 4 H)*, 2.22(s, 6 H), 2.22 (s, 6 H)*, 2.13 (m, 2 H), 2.13 (m, 2 H)*, 1.99 (m, 2 H),1.99 (m, 2 H)*, 1.82 (m, 2 H), 1.82 (m, 2 H)*, 1.64 (m, 2 H), 1.64 (m, 2H)* (note: * denotes peaks derived from the minor tautomer): [M+1]⁺ 418.

EXAMPLE 6

2-Cyclopentyl-9-(1-Methyl-1H-Pyrazol-4-Yl)-3,6-Dihydro-7H-Benzo[H]Imidazo[4,5-F]Isoquinolin-7-OneStep A:2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

9-Bromo-2-(2-chlorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one(30 mg, 0.071 mmol), lithium chloride (6 mg, 0.14 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (30mg, 0.14 mmol), and tetrakis(triphenylphosphine)palladium(0) (8 mg,0.0071 mmol) were placed in a microwave tube. Na₂CO₃ (2 M, 0.25 mL) andDMF (1 mL) were added and the solution was heated in the microwave at130° C. for ten minutes. The solution was cooled to ambient temperaturediluted with ethyl acetate and Na₂CO₃ (2 M). The organic layer wasseparated, washed with brine, dried over MgSO₄, filtered andconcentrated to dryness. The crude residue was purified on silica gel toafford the title compound. ¹H NMR (500 MHz, DMSO-d₆, δ_(H)) 11.56 (bs, 1H), 10.49 (bs, 1 H), 8.56-8.45 (m, 1 H), 8.18 (s, 1 H), 7.90-7.87 (m, 3H), 7.69 (d, 1 H, J=7.2 Hz), 7.58-7.54 (m, 3H), 7.34-7.28 (m, 1 H):[M+1]⁺ 426.1.

EXAMPLE 7

2-(2-Chloro-6-Fluorophenyl)-9-(6-Chloropyridin-3-Yl)-3,6-Dihydro-7H-Benzo[H]Imidazo[4,5-F]Isoquinolin-7-OneStep A:2-(2-chloro-6-fluorophenyl)-9-(6-chloropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

9-Bromo-2-(2-chloro-6-fluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one(500 mg, 1.130 mmol) was dissolved in ethanol (15 ml) and toluene (15.00ml). (Dichlorobis)palladiumtriphenylphosphine (79 mg, 0.113 mmol),2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (298mg, 1.242 mmol) and Na₂CO₃ (2 M, 1.135 mL) were added and argon wasbubbled through the solution for several minutes. The solution washeated at 80° C. for 2 hours. The reaction mixture was cooled to ambienttemperature and diluted with ethyl acetate and water. The organic layerwas separated, dried over magnesium sulftate, filtered and concentrated.The crude residue was purified via a chiral AD column which afforded thetitle compound. ¹H NMR (500 MHz, CD₃OD, δ_(H)) 10.68 (s, 1 H), 8.56 (d,1 H, J=1.8 Hz), 8.30 (dd, 1 H, J=8.4, 3.0 Hz), 8.04 (dd, 1 H) J=9.0, 1.8Hz), 7.68-7.64 (m, 1 H), 7.63-7.60 (m, 2 H), 7.54 (d, 1 H, J=8.4 Hz),7.38 (td, 1 H, J =9, 1.2 Hz): [M+1]⁺ 475.

EXAMPLE 8

N′-[2-(2-Chloro-6-Fluorophenyl)-7-Oxo-6,7-Dihydro-3H-Benzo[H]Imidazo[4,5-F]Isoquinolin-9-Yl]-N,N-Dimethylsulfamide

Step A:9-bromo-2-(2-chloro-6-fluorophenyl)-3,6-bis{[2-(trimethylsilyl)ethoxy]methyl}-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

The intermediate from Example 1 Step E (1.76 g, 3.99 mmol) was suspendedin 150 mL THF and the flask was immersed in a room temperature waterbath followed by the addition 11 mL (2.7 equiv) of a 1M solution ofpotassium tert-butoxide (in THF). After 45 minutes, 1.79 g of SEMCl (2.7equiv) was added. The reaction was allowed to warm to ambienttemperature overnight. The volatiles were removed in vacuo and the cruderesidue was dissolved in EtOAc and washed sequentially with a saturatedsolution of NaHCO₃ and brine. The solution was dried with MgSO₄ andfiltered. Evaporation of the solvent under reduced pressure provided thecrude residue that was purified on silica gel (gradient elution from 0to 30% EtOAc/hexanes).

Step B:N′-(2-(2-chloro-6-fluorophenyl)-7-oxo-3,6-bis{[2-trimethylsilyl)ethoxy]methyl}-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl)-N,N-dimethylsulfamide

The intermediate from Example 8 Step A (300 mg, 0.4240 mmol) wascombined in a microwave vial with N,N-dimethylsulfamide (50 mg, 0.4027mmol), Cs₂CO₃ (400 mg, 1.228 mmol), Pd₂(dba)₃ (20 mg, 0.0218 mmol), andXantphos (36 mg, 0.0622 mmol). The vial was evacuated and purged withargon several times and the vial was sealed. Dioxane (10 mL) was addedand the mixture was heated to 100° C. overnight. The reaction was cooledto ambient temperature and diluted with EtOAc and washed sequentiallywith a saturated solution of NaHCO₃ and brine. The solution was driedwith MgSO₄ and filtered. Evaporation of the solvent under reducedpressure provided the crude residue that was purified on silica gel(gradient elution from 10 to 50% EtOAc/hexanes): [M+1]⁺ 747.

Step C:N′-[2-(2-chloro-6-fluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[H]imidazo[4,5-f]isoquinolin-9-yl]-N,N-dimethylsulfamide

The intermediate from Example 8 Step B (100 mg, 0.1340 mmol) wasdissolved in 5 mL THF and treated with 5 equiv of a 1M solution of TBAF(in THF). The mixture was heated to 150° C. in a microwave for 15minutes. The reaction was cooled to ambient temperature and diluted withEtOAc and washed sequentially with water and brine. The solution wasdried with MgSO₄ and filtered. Evaporation of the solvent under reducedpressure provided the crude residue that was purified on silica gel(gradient elution from 0 to 100% EtOAc/hexanes): [M+1]⁺ 486.

EXAMPLE 9

2-(2,6-Difluorophenyl)-9-[(Tetrahydrofuran-3-Ylmethyl)Amino]-3,6-Dihydro-7H-Benzo[H]Imidazo[4,5-F]Isoquinolin-7-One

Step A:4-[4-(4-bromophenyl)-2-(2,6-difluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one

Using the general procedure found in Example 1 Step C, the intermediatefrom Example 1 Step B was combined with 2,6-difluorbenzaldehyde,ammonium acetate, and acetic acid: [M+1]⁺ 444.

Step B:4-[4-(4-bromophenyl)-2-(2,6-difluorophenyl)-1H-imidazol-5-yl]pyridin-2(1H)-one

Using the general procedure in Example 1 Step D, the intermediate ofExample 9 Step A was treated with TiCl₃ in methanol to provide the titlecompound: [M+1]⁺ 428.

Step C:9-bromo-2-(2,6-difluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

A solution of the intermediate in Example 9 Step B (12 g, 28 mmol) inTHF (2 L) was stirred under irradiation of UV lamp for 30 h. The solventwas removed in vacuo. The crude residue was crystallized from methanolto afford the title compound. ¹H NMR (DMSO, 400 MHz) δ14.06 (s, 1H),11.81 (s, 1H), 10.55 (s, 1H), 8.39 (d, J=8.6Hz, 1H), 7.81˜7.89 (m, 1H),7.58˜7.72 (m, 2H), 7.19˜7.40 (m, 3H): [M+1]⁺ 426.

Step D:2-(2,6-difluorophenyl)-9-[(tetrahydrofuran-3-ylmethyl)amino]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

A 0.5-2 mL microwave vial containing a stir bar was placed under argonby attaching a rubber septum and performing 4 vacuum/argon cycles. Theintermediate from Example 9 Step C (100 mg, 0.146 mmol), sodiumtert-butoxide (20.99 mg, 0.218 mmol), 2-(di-tert-butylphosphino)biphenyl(8.7 mg, 0.029 mmol), Pd₂(dba)₃ (13.33 mg, 0.015 mmol) were added, andthe vial was sealed. While adding the solids to the vial, 30 mL oftoluene was deoxygenated by bubbling argon through for 30 minutes; 1.0mL of this was added to the sealed reaction vial.3-(Aminomethyl)tetrahydrofuran (0.024 ml, 0.204 mmol) was added viamicrosyringe, and then argon was flushed gently through the vial for 5min. The reaction was heated to 90° C. for 15 hours and then cooled toroom temperature. A solution of tetrabutylammonium fluoride (1 Mintetrahydrofuran, 0.710 ml, 0.710 mmol) was added, and the vial washeated in a microwave oven for 10 min at 150° C. After cooling to roomtemperature, the reaction mixture was partitioned between a 1:1 mixtureof EtOAc:ether (20 mL) and water (10 mL). The layers were separated, andthe organic layer was washed sequentially with water (10 mL), saturatedNaHCO₃ (10 mL), and brine (10 mL), dried over Na₂SO₄, filtered, andconcentrated. The resulting solid was purified by reverse phase HPLC.After lypophilization, the title compound was obtained. ¹H NMR (600 MHz,DMSO) δ: 11.44 (s, 1 H), 9.57 (s, 1 H), 8.22 (m, 1 H), 7.68 (m, 1 H),7.49 (t, 1 H, J=6.3 Hz), 7.38 (t, 2 H, J=8.2Hz), 7.16 (d, 2 H, J=5.6Hz), 3.78 (m, 2 H), 3.64 (q, 1 H, J=7.6 Hz), 3.51 (dd, 1 H, J=8.5, 5.6Hz), 3.17 (m, 2 H), 2.60 (m, 1 H), 2.04 (m, 1 H), 1.66 (m, 1 H): [M+1]⁺447.

EXAMPLE 10

9-(5-Chloropyridin-2-Yl)-2-(2,6-Difluorophenyl)-3,6-Dihydro-7H-Benzo[H]Imidazo[4,5-F]Isoquinolin-7-One

Step A:2-(2,6-difluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

The intermediate from Example 9 Step C (250 mg, 0.59 mmol), Cy₃P (19.7mg, 0.07 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2,-bi-1,3,2-dioxaborolane (149 mg, 0.59mmol), potassium acetate (144 mg, 1.47 mmol), and Pd₂(dba)₃ (26.9 mg,0.03 mmol) were added to a sealed dry flask with stir bar. The flask wasevacuated and back-filled with argon three times. Fully degassed dioxane(5.9 ml) was added. The flask was sealed and placed in an oil bath at90° C. and stirred overnight. The mixture was filtered over a thin layerof celite, eluted with dichloromethane, partially rotovaped to removesome of the dichloromethane, and then triturated with hexanes. Theprecipitate was filtered to afford an off white solid. ¹H NMR (600 MHz,CD₃OD) δ 10.72 (s, 1H); 8.33 (s, 1H); 8.03 (dd, 1H); 7.66 (m, 2H); 7.58(m, 2H); 7.27 (m, 3H); 1.40 (s, 12H): [M+H]⁺ 474.

Step B:9-(5-chloropyridin-2-yl)-2-(2,6-difluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

To a pressure flask with stir bar, the intermediate from Example 10 StepA (75mg, 0.16 mmol), 2-bromo-5-chloropyridine (33.5 mg, 0.17 mmol), and(Ph₃P)₂PdCl₂ (11.1 mg, 0.02 mmol) were added. The flask was purged ofair and back-filled with argon (3×). Toluene (0.79 ml) and ethanol (0.79ml) were bubbled with argon for at least 10 min before addition to theflask. Na₂CO₃ (0.24 ml, 0.48 mmol) was bubbled with argon, and thenadded to the flask. The mixture was heated at 90° C. in an oil bathovernight. Water was added to quench the reaction. The water layer wasextracted with ethyl acetate 3×. The combined organics were washed withbrine, dried with MgSO₄, filtered, and concentrated in vacuo. The crudecompound was purified by reverse phase HPLC (10-100% acetonitrile inH₂O+0.05% TFA) to afford a light yellow solid. ¹H NMR (600 MHz, CD₃OD) δ14.00 (m, 1H), 11.40 (m, 1H), 10.97 (s, 1H), 8.73 (s, 1H); 8.53 (d, 1H);8.29 (s, 1H); 8.05 (s, 2H); 7.56 (m, 3H); 7.25 (d, 2H): [M+H]⁺ 459.

EXAMPLE 112-(2-Chloro-6-Fluorophenyl)-9-(2,6-Difluoropyridin-3-Yl)-3,6-Dihydro-7H-Benzo[H]Imidazo[4,5-F]Isoquinolin-7-One

Step A:2-(2-chloro-6-fluorophenyl)-9-(2,6-difluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

A sealed tube was charged with the intermediate from Example 1 Step E(230 mg, 0.52 mmol), (2,6-difluoropyridin-3-yl)boronic acid (580 mg, 3.6mmol), and bis(triphenylphosphine)palladium(n) chloride (73 mg, 0.1mmol). The tube was evacuated and backfilled with argon three times.Fully degassed toluene (3.0 mL) and ethanol (3.0 mL) were added,followed by the addition of 2.0M aqueous sodium carbonate solution (2.6mL, 5.2 mmol). The tube was sealed, placed in an oil bath at 90° C., andstirred for 3 hours. The reaction mixture was then cooled and pouredinto a mixture of ethyl acetate and brine. The aqueous layer wasextracted twice with ethyl acetate and the combined organics were driedover magnesium sulfate, filtered, concentrated in vacuo. Purificationvia flash chromatography (silica, 0-20% methanol/dichloromethane) wasfollowed by purification via preparative chiral HPLC (AD column, 25%ethanol/heptane isocratic) to afford the title compound. ¹H NMR (600MHz, d6-DMSO) δ 11.75 (s, 1H), 10.57 (s, 1H), 8.49 (broad s, 1H), 8.43(q, 1H), 7.92 (d, 1H), 7.72-7.69 (m, 1H), 7.62-7.61 (m, 2H), 7.58-7.52(m, 1H), 7.37 (dd, 1H), 7.27 (broad s, 1H). Imidazole proton was notobserved [M+H]⁺ 476. τ_(R): 9.44 min (analytical chiral HPLC, AD column,0.46 cm×25 cm, 25% ethanol/heptane, isocratic, flow rate=0.75 mL/min).

Additional analogues were prepared using procedures similar to thosedescribed in the above examples.

Compound Name R1 R2 M + 1 9-bromo-2-(2-chlorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5- f]isoquinolin-7-one

Br 425 9-bromo-2-(tetrahydro-2H-pyran- 4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5- f]isoquinolin-7-one

Br 398 9-bromo-2-(tetrahydrofuran-3-yl)- 3,6-dihydro-7H-benzo[h]imidazo[4,5- f]isoquinolin-7-one

Br 384 9-bromo-2-(tetrahydro-2H-pyran- 3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5- f]isoquinolin-7-one

Br 398 9-bromo-2-(2,2- dimethyltetrahydro-2H-pyran-4-yl)-3,6-dihydro-7H- benzo[h]imidazo[4,5- f]isoquinolin-7-one

Br 426 9-bromo-2-(1-isopropyl-1H- pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5- f]isoquinolin-7-one

Br 422 9-bromo-2-pyridin-3-yl-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

Br 391 9-bromo-2-(1,5-dimethyl-1H- pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5- f]isoquinolin-7-one

Br 408 9-bromo-2-isoquinolin-8-yl-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

Br 441 9-bromo-2-isoquinolin-5-yl-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

Br 441 9-bromo-2-cyclopentyl-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

Br 382 9-bromo-2-(2-chloro-6- fluorophenyl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

Br 442 9-bromo-2-(3-chloropyridin-4- yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

Br 365 9-bromo-2-(1-phenylethyl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

Br 418 9-bromo-2-(2-chloro-4- fluorophenyl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

Br 442 9-bromo-2-(2,4,6- trifluorophenyl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

Br 444 9-bromo-2-(2,6-difluorophenyl)- 3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

Br 426 9-bromo-2-(trifluoromethyl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

Br 382 2-cyclopentyl-9-(isobutylamino)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

375 2-cyclopentyl-9-{[(1,5-dimethyl- 1H-pyrazol-3-yl)methyl]amino}-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

427 9-{[1-(4- chlorophenyl)ethyl]amino}-2- cyclopentyl-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

456 2-cyclopentyl-9- [(tetrahydrofuran-2- ylmethyl)amino]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

403 2-cyclopentyl-9-[(2- methoxyethyl)amino]-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

377 2-cyclopentyl-9-[(2-hydroxy-2- phenylethyl)(methyl)amino]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

453 2-cyclopentyl-9-[(2R)-2- phenylmorpholin-4-yl]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

465 2-cyclopentyl-9-[(3R)-3- methoxypyrrolidin-1-yl]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

403 2-(2,6-difluorophenyl)-9- [(tetrahydrofuran-2- ylmethyl)amino]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

447 N′-[2-(2-chloro-6-fluorophenyl)- 7-oxo-6,7-dihydro-1H-benzo[h]imidazo[4,5- f]isoquinolin-9-yl]-N,N- dimethylsulfamide

486 2-(2,6-difluorophenyl)-9-{[(3- methyloxetan-3- yl)methyl]amino}-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

447 2-(2,6-difluorophenyl)-9- [(tetrahydrofuran-3- ylmethyl)amino]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

447 2-(2,6-difluorophenyl)-9-{[(2- methyltetrahydrofuran-2-yl)methyl]amino}-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

461 2-(2,6-difluorophenyl)-9-[(1,4- dioxan-2-ylmethyl)amino]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

463 3-{[2-(2,6-difluorophenyl)-7-oxo- 6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinolin-9- yl]amino}propanenitrile

416 2-(2,6-difluorophenyl)-9-{[2-(1H- imidazol-4-yl)ethyl]amino}-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

457 9-[(2,4-difluorobenzyl)amino]-2- (2,6-difluorophenyl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

489 2-(2,6-difluorophenyl)-9-{[2- (pyridin-2-ylamino)ethyl]amino}- 3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

483 2-(2,6-difluorophenyl)-9-[(2,3- dihydroxypropyl)amino]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

437 2-(2-chlorophenyl)-9-(1-methyl- 1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

426 2-(2-chlorophenyl)-9-pyridin-4- yl-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

423 tert-butyl 4-{4-[2-(2- chlorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinolin-9- yl]phenyl}piperazine-1-carboxylate

606 2-(2-chlorophenyl)-9-(4- piperazin-1-ylphenyl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

2-(2-chlorophenyl)-9-[3- (dimethylamino)phenyl]-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

465 9-biphenyl-3-yl-2-(2- chlorophenyl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

499 9-biphenyl-2-yl-2-(2- chlorophenyl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

499 2-(2-chlorophenyl)-9-pyridin-3- yl-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

423 4-[2-(2-chlorophenyl)-7-oxo-6,7- dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]-N,N- dimethylbenzamide

493 4-[2-(2-chlorophenyl)-7-oxo-6,7- dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]-N-[2- (dimethylamino)ethyl]benzamide

536 2-(2-chlorophenyl)-9-{4-[(4- methylpiperazin-1-yl)carbonyl]phenyl}-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

548 2-(2-chlorophenyl)-9-[2-(4- methylpiperazin-1-yl)pyridin-4-yl]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

521 2-(2-chlorophenyl)-9-[4- (morpholin-4-ylcarbonyl)phenyl]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

535 N-{3-[2-(2-chlorophenyl)-7-oxo- 6,7-dihydro-3H- benzo[h]imidazo[4,5-f]isoquinolin-9- yl]phenyl}methanesulfonamide

515 N-{4-[2-(2-chlorophenyl)-7-oxo- 6,7-dihydro-3H- benzo[h]imidazo[4,5-f]isoquinolin-9- yl]phenyl}methanesulfonamide

515 2-(2-chlorophenyl)-9-(4- methoxyphenyl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

452 2-(2-chlorophenyl)-9-(3- methoxyphenyl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

452 2-(2-chlorophenyl)-9-(2- methoxyphenyl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

452 4-[2-(2-chlorophenyl)-7-oxo-6,7- dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]-N- ethylbenzamide

493 4-[2-(2-chlorophenyl)-7-oxo-6,7- dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]-N- isobutylbenzamide

521 2-(2-chlorophenyl)-9-quinolin-5- yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

473 2-(2-chlorophenyl)-9-(1H- pyrazol-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5- f]isoquinolin-7-one

412 2-(2-chlorophenyl)-9-[6-(4- methylpiperazin-1-yl)pyridin-3-yl]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

521 2-cyclopentyl-9-(1H-pyrazol-3- yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

370 2-(2-chloro-6-fluorophenyl)-9-[4- (morpholin-4-ylcarbonyl)phenyl]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

553 9-(1H-pyrazol-3-yl)-2- (tetrahydrofuran-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5- f]isoquinolin-7-one

372 2-cyclopentyl-N-[2- (dimethylamino)ethyl]-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinoline-9-carboxamide

418 2-cyclopentyl-N-(3-methylbutyl)- 7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinoline-9-carboxamide

417 2-cyclopentyl-9-[(4- methylpiperazin-1-yl)carbonyl]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

430 2-cyclopentyl-9-(morpholin-4- ylcarbonyl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

417 2-cyclopentyl-9-[(4- hydroxypiperidin-1-yl)carbonyl]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

431 2-cyclopentyl-9-(piperidin-1- ylcarbonyl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

415 2-cyclopentyl-7-oxo-N-(pyridin- 2-ylmethyl)-6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinoline-9-carboxamide

438 2-cyclopentyl-7-oxo-N-(pyridin- 3-ylmethyl)-6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinoline-9-carboxamide

438 2-cyclopentyl-N- (methylsulfonyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinoline-9-carboxamide

425 N-benzyl-2-cyclopentyl-7-oxo- 6,7-dihydro-3H- benzo[h]imidazo[4,5-f]isoquinoline-9-carboxamide

437 9-(1H-pyrazol-3-yl)-2- (tetrahydrofuran-3-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

372 2-cyclopentyl-9-(6- methoxypyridin-3-yl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

411 2-cyclopentyl-9-(1H-pyrazol-4- yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

370 2-cyclopentyl-9-(2,6- dimethoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

441 2-cyclopentyl-9-pyrimidin-5-yl- 3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

382 2-cyclopentyl-9-(3,5- dimethylisoxazol-4-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

399 2-(2-chloro-6-fluorophenyl)-9- (1H-pyrazol-3-yl)-1,6-dihydro-7H-benzo[h]imidazo[4,5- f]isoquinolin-7-one

430 2-(2-chloro-6-fluorophenyl)-9- (1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

430 2-(2-chloro-6-fluorophenyl)-9- pyridin-3-yl-1,6-dihydro-7H-benzo[h]imidazo[4,5- f]isoquinolin-7-one

441 2-(2-chloro-6-fluorophenyl)-9-(4- morpholin-4-ylphenyl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

525 2-(2-chloro-6-fluorophenyl)-9-(2- morpholin-4-ylpyridin-4-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

526 2-(2-chloro-6-fluorophenyl)-9- pyridin-4-yl-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

441 9-(6-aminopyridin-3-yl)-2-(2- chloro-6-fluorophenyl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

456 2-(2-chloro-6-fluorophenyl)-9-(6- methoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

471 2-(2-chloro-6-fluorophenyl)-9-(4- methoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

471 2-(2-chloro-6-fluorophenyl)-9-{6- [(2-morpholin-4-ylethyl)amino]pyridin-3-yl}-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

469 2-(2-chloro-6-fluorophenyl)-9-(6- hydroxypyridin-3-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

457 2-(2-chloro-6-fluorophenyl)-9-(5- chloro-2-methoxypyridin-4-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

505 2-(2-chloro-6-fluorophenyl)-9-(6- chloropyridin-3-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

475 N-{3-[2-(2-chloro-6- fluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinolin-9-yl]pyridin-2-yl}-2,2-dimethylpropanamide

540 2-(2-chloro-6-fluorophenyl)-9-[2- (cyclopropylmethoxy)pyridin-3-yl]-3,6- dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

511 2-(2-chloro-6-fluorophenyl)-9-(6- fluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

459 5-[2-(2-chloro-6-fluorophenyl)-7- oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinolin-9-yl]pyridine-2- carbonitrile

466 2-(2-chloro-6-fluorophenyl)-9- (2,6-difluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

477 2-(2-chloro-6-fluorophenyl)-9-(6- methylpyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5- f]isoquinolin-7-one

455 2-(2-chloro-6-fluorophenyl)-9- pyrimidin-5-yl-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

442 2-(2-chloro-6-fluorophenyl)-9- quinolin-3-yl-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

491 2-(2-chloro-6-fluorophenyl)-9-[6- (dimethylamino)pyridin-3-yl]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

484 2-(2-chloro-6-fluorophenyl)-9-(3- furyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

430 2-(2-chloro-6-fluorophenyl)-9-(1- methyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

444 9-(4-aminophenyl)-2-(2-chloro-6- fluorophenyl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

455 9-(3-aminophenyl)-2-(2-chloro-6- fluorophenyl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

455 2-(2-chloro-6-fluorophenyl)-9-[4- (dimethylamino)phenyl]-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

483 2-(2-chloro-6-fluorophenyl)-9-{2- [(dimethylamino)methyl]phenyl}-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

497 2-(2-chloro-6-fluorophenyl)-9- (2,6-dimethoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

501 2-(2-chloro-6-fluorophenyl)-9- (3,5-dimethyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

458 2-(2-chloro-6-fluorophenyl)-9- (1,3,5-trimethyl-1H-pyrazol-4-yl)-3,6- dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

472 2-(2-chloro-6-fluorophenyl)-9- isoquinolin-4-yl-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

491 2-(2-chloro-6-fluorophenyl)-9-(2- methoxypyrimidin-5-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

472 2-(2-chloro-6-fluorophenyl)-9-(6- morpholin-4-ylpyridin-3-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

526 2-(2-chloro-6-fluorophenyl)-9-(2- methoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

471 2-(2-chloro-6-fluorophenyl)-9-(2- fluoroquinolin-3-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

510 N-{3-[2-(2-chloro-6- fluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinolin-9- yl]phenyl}acetamide

497 N-{3-[2-(2-chloro-6- fluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinolin-9- yl]phenyl}methanesulfonamide

533 N-{4-[2-(2-chloro-6- fluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinolin-9- yl]phenyl}methanesulfonamide

533 3-[2-(2-chloro-6-fluorophenyl)-7- oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinolin-9-yl]benzamide

483 4-[2-(2-chloro-6-fluorophenyl)-7- oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinolin-9-yl]benzamide

483 2-(2,6-difluorophenyl)-9-(1- methyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

428 2-(2,6-difluorophenyl)-9-(6- fluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

443 2-(2,6-difluorophenyl)-9-(3,4- difluorophenyl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

460 4-[2-(2,6-difluorophenyl)-7-oxo- 6,7-dihydro-3H-benzo[h]imidazo[4,5- f]isoquinolin-9-yl]-2- fluorobenzonitrile

467 2-(2,6-difluorophenyl)-9-(2,3,4- trifluorophenyl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

478 2-(2,6-difluorophenyl)-9-(2- fluoropyridin-4-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

443 2-(2,6-difluorophenyl)-9-(5- fluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

443 2-(2,6-difluorophenyl)-9-(5- fluoropyridin-2-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

443 2-(2,6-difluorophenyl)-9-(3- fluoropyridin-4-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

443 9-(2-chloropyridin-4-yl)-2-(2,6- difluorophenyl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

459 2-(2,6-difluorophenyl)-9-(6- fluoropyridin-2-yl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

443 9-(5-chloropyridin-2-yl)-2-(2,6- difluorophenyl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

459 2-(2,6-difluorophenyl)-9-(6- methoxypyridin-2-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5- f]isoquinolin-7-one

455 2-(2,6-difluorophenyl)-9-pyridin- 2-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

425 9-[4-(methylsulfonyl)phenyl]-2- (trifluoromethyl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

458 9-(1-methyl-1H-pyrazol-4-yl)-2- (trifluoromethyl)-3,6-dihydro-7H-benzo[h] imidazo[4,5-f]isoquinolin-7-one

384 9-{4-[(4-methylpiperazin-1- yl)carbonyl]phenyl}-2-(trifluoromethyl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

506 9-[2-(4-methylpiperazin-1- yl)pyridin-4-yl]-2-(trifluoromethyl)-3,6- dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one

479Pharmaceutical Composition

As a specific embodiment of this invention, 100 mg of9-bromo-2-(2-chlorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one,is formulated with sufficient finely divided lactose to provide a totalamount of 580 to 590 mg to fill a size 0, hard-gelatin capsule.

Biological Assays

JAK2 Kinase Activity Inhibition Assay and Determination of IC₅₀

The kinase activity was measured using a modified version of thehomogeneous time-resolved tyrosine kinase assay described in Park et al.Anal. Biochem. 269, 94-104 (1999).

The procedure for determining the potency of a compound to inhibit JAK2kinase comprises the following steps:

-   -   1. prepare 3-fold serial diluted compound/inhibitor solutions in        100% (DMSO) at 20× of the final desired concentrations in a 96        well plate;    -   2. prepare a master reaction mix containing 6.67 mM MgCh, 133.3        mM NaCl, 66.7 mM Tris-HCl (pH 7.4), 0.13 mg/ml BSA, 2.67 mM        dithiothreitol, 0.27 recombinant JAK2 and 666.7 nM biotinylated        synthetic peptide substrate (biotin-ahx-EQEDEPEGDYFEWLE-CONH₂)        (SEQ. ID.: 1);    -   3. in a black assay plate, add 2.5 μl compound/inhibitor (or        DMSO) and 37.5 μl master reaction mix per well; initiate the        kinase reaction by adding 10 μl of 75 μM MgATP per well, allow        the reactions to proceed for 80 minutes at room temperate; (the        final conditions for the reactions are: 50 nM JAK2 JH1 domain        (Upstate), 2.0 μM substrate, 15 μM MgATP, 5 mM MgCl₂, 100 mM        NaCl, 2 mM DTT, 0.1 mg/ml BSA, 50 mM Tris (pH 7.4) and 5% DMSO);    -   4. stop the kinase reaction with 50 μl of Stop/Detection buffer        containing 10 mM EDTA, 25 mM HEPES, 0.1% TRITON X-100, 0.126        μg/ml Eu-chelate labeled anti-phosphotyrosine antibody PY20        (cat. # AD0067, PerkinElmer) and 45 μg/ml        Streptavidm-allophycocyanin conjugate (cat. #PJ25S, Prozyme);        and    -   5. read HTRF signals on a Victor reader (PerkinElmer) in HTRF        mode after 60 minutes.

IC₅₀ was obtained by fitting the observed relationship betweencompound/inhibitor concentration and HTRF signal with a 4-parameterlogistic equation.

Compounds of the instant invention are potent inhibitors of recombinantpurified JAK2 kinase activity with an IC₅₀ of approximately 0.1 nM-20μM.

JAK1 Enzyme Assay

For the JAK1 enzyme assay, reactions (50 uL) contained 5× IVGN buffer(50 mM Hepes, pH 7.5, 10 mM MgCl2, 0.01% Brij-35, 1 mM EGTA, 0.1 mg/mlBSA), 2 mM DTT, 2.0 μM peptide substrate, 25 μM MgATP, 400 pM JAK1enzyme and subject compound in 5% DMSO. Reactions were incubated for 60min at RT and quenched with 50 μL 2× quench detect buffer (10 mM EDTA,25 mM HEPES, 0.1% TRITON X-100, 4.7 uM Europium-Py20 and 2.1 mg/mLstreptavidin-APC). Incubate 1 hr at RT and read on a Victor V3 set toread Fluorescent Resonance Energy Transfer (Label 1: Lance 615, Label 2:Lance 665, For both: delay=50 us, window time=100 us, cycle=1000 us,flash energy level=103)

Peptide substrate is amino hexanoyl biotin-EQEDEPEGDYFEWLE-NH2 (SEQ.ID.: 1); in DMSO.

TYK2 Enzyme Assay

For the TYK2 enzyme assay, reactions (50 uL) contained 5× IVGN buffer(50 mM Hepes, pH 7.5, 10 mM MgCl2, 0.01% Brij-35, 1 mM EGTA, 0.1 mg/mlBSA), 2 mM DTT, 2.0 μM peptide substrate, 15 μM MgATP, 125 pM enzyme andsubject compound in 5% DMSO. Reactions were incubated for 60 min at RTand quenched with 50 uL 2× quench detect buffer (10 mM EDTA, 25 mMHEPES, 0.1% TRITON X-100, 4.7 uM Europium-Py20 and 2.1 mg/mLstreptavidin-APC). Incubate 1 hr at RT and read on a Victor V3 set toread Fluorescent Resonance Energy Transfer (Label 1: Lance 615, Label 2:Lance 665, For both: delay=50 us, window time=100 us, cycle=1000 us,flash energy level=103)

Peptide substrate is amino hexanoyl biotin-EQEDEPEGDYFEWLE-NH2 (SEQ.ID.: 1);in DMSO.

Assay For JAK Family Protein Kinase Activity

-   Materials. Streptavidin•allophycocyanin conjugate (SA•APC) and    Europium•cryptate (Eu•K) were from Packard Instrument Company. Eu•K    conjugated pY20 was produced as described in Cummings, R. T.;    McGovern, H. M.; Zheng, S.; Park, Y. W. and Hermes, J. D. Use Of A    Phosphotyrosine-Antibody Pair As A General Detection Method In    Homogeneous Time Resolved Fluorescence-Application To Human    Immunodeficiency Viral Protease. Analytical Biochemistry 1999, 33,    79-93. Homogenous time resolved fluorescence (HTRF) measurements    were made using the Discovery instrument from Packard. T-stim    Culture Supplement was from Collaborative Biomedical Research.    Recombinant mouse IL2 was from Pharmingen or R & D.-   JAK family kinase expression. JAK3, TYK2 and JAK2 kinase domains    with N-terminal “Flag” affinity tags were expressed in Sf9 cells    using standard baculovirus methods. The human JAK3 gene was provided    by Dr. John J. O'Shea (NTH). The human TYK2 gene was provided by Dr.    Sandra Pellegrini (Insitut Pasteur). Human JAK2 kinase domain was    cloned from a MOLT4cDNA library (Clonetech).-   Assay for JAK family protein kinase activity. Tyrosine kinase    activity was measured by detection of the tyrosine phosphorylated    peptide amino hexanoyl biotin-EQEDEPEGDYFEWLE-NH₂ (SEQ. ID.: 1); (S,    hereafter) detected by time-resolved fluorescence using a europium    labeled antibody to phosphotyrosine (pY20). The JAK3(JH1) catalyzed    phosphorylation reactions were carried out in a 30 uL total reaction    volume. The compound was run at 5% DMSO and preincubated with enzyme    buffer (EB). The EB comprised Invitrogen 5× kinase buffer (50 mM    Hepes, pH 7.5, 10 mM MgCl2, 0.01% Brij-35, 1 mM EGTA, 0.1 mg/ml    BSA), 2 mM (final) DTT, 2 μM (final) S, and 250 pM (final) JAK3    enzyme. The assay was run at ATP K_(m) (5 μM final) for 40 to 80    minutes. Reactions were run at ambient temperature and quenched with    an equal volume of quench buffer (QB) (10 mM EDTA, 25 mM HEPES, 0.1%    TRITON X-100) containing 50 μg/mL SA•APC conjugate and 0.75 nM Eu•K    conjugated pY20. This mixture was incubated at ambient temperature    for at least 60 minutes and read on an optimized fluorescent reader    at Ex=320nm and Em₁=665 nm (SA−APC) and Em₂=615 nM (Eu). The data    was analyzed by using a standard 4P fit on the ratio of the Em    results: (EM₁÷EM₂)*10,000.-   Cellular proliferation assays. CTLL-2 cells (ATCC) were maintained    in 6% T-stim Culture Supplement (source of IL2) in RPMI-1640    supplemented with 10% fetal bovine serum, 1 mM sodium pyruvate, 50    μM β-mercaptoethanol, 1.4 mM L-glutamine, 10 mM HEPES, 1 mg/ml    dextrose, 0.04 mM essential amino acids, 0.02 mM nonessential amino    acids, penicillin and streptomycin (H10). The day before use in the    proliferation assay, cells were washed and resuspended in 0.2% Tstim    at a cell concentration of 5×10⁵/ml. The next day, cells were washed    and plated at 0.2-1×10⁵ cells/well in a 96 well tissue culture plate    (CoStar). 0.05 ng/ml mouse recombinant IL2 (Pharmingen), with or    without a test compound, or 20 ng/ml PMA (Sigma) and 1 μCi/well    [³H]-thymidine were added. After overnight culture, cells were    harvested with a glass fiber Filtermat (Wallac) and a Tomtek cell    harvester. Tritium incorporation was measured by liquid    scintillation counting on a Topcount scintillation counter    (Packard).

Compounds of the instant invention are potent inhibitors of recombinantpurified JAK3 kinase activity with an IC₅₀ of approximately 0.1 nM-20μM.

In vitro PDK1 Kinase Assay

Activated recombinant full-length mT(Glu-Glu-Phe) tagged human PDK1 isused to determine whether the compounds of the instant inventionmodulate the enzymatic activity of this kinase.

The cDNA, encoding full-length PDK1, is subcloned into a baculovirusexpression vector pBlueBac4.5 (Invitrogen), containing an in framemiddle T tag (MEYMPME) at its N-terminus. Soluble activated recombinantfull-length mT(Glu-Glu-Phe) tagged human PDK1 is expressed in abaculovirus-infected Sf9 insect cells (Kemp Biotechnologies), accordingto the protocol recommended by the manufacturer. Immunoaffinitypurification of the PDK1 kinase from the insect cell lysate is performedusing a middle Tag antibody bound to Protein G-EE column. Upon elutionusing 50 mM Tris pH 7.4, 1 mM EDTA, 1 mM EGTA, 0.5 mM Na₃VO₄, 1 mM DTT,50 mM NaF, Na Pyrophospate, Na-β-glycerophosphate, 10% glycerol,Complete, 1 μM microcystein, and 50 μg/ml EYMPME peptide, fractionscontaining PDK1 protein are pooled together, based on SDS-PAGE andwestern blot analyses, and then analyzed for protein concentration usingBCA Protein Assay (Pierce) with BS A as standard. The final product wasaliqouted and flash frozen in liquid nitrogen before being stored at−80° C. Resulting PDK1 protein has MW of 64 kDa, is phosphorylated ‘bydefault’ and purifies as an activated kinase from insect cells.

The procedure for determining the potency of a compound to inhibit PDK1kinase comprises the following steps:

-   -   1. Prepare 3-fold serial diluted compound solutions in 100%        dimethyl sulfoxide (DMSO) at 20× of the desired final        concentrations in a 384-well plate.    -   2. Prepare a master reaction mix containing 62.5 mM HEPES (pH        7.5), 12.5 mM MgCl₂, 0.013% Brij-35, 1.25 mM EGTA, 2.5 mM        dithiothreitol, 1.25 nM recombinant PDK1and 375 nM biotinylated        synthetic peptide substrate        (Biotin-GGDGATMKTFCGGTPSDGDPDGGEFTEF-COOH) (SEQ. ID.: 2).    -   3. In a black assay plate, add 2.5 μl of compound solution (or        DMSO) and 22.5 μl of master reaction mix per well. Pre-incubate        for 10 min. Initiate the kinase reaction by adding 6 μl of 0.25        mM MgATP per well. Allow the reactions to proceed for 25 min at        room temperature. The final conditions for the reaction are 1 nM        PDK1, 300 nM peptide substrate, 5 uM MgATP, 10 mM MgCl₂, 2 mM        DTT, 50 mM HEPES (pH 7.5), 0.01% Brij-35, 1 mM EGTA and 5% DMSO.    -   4. Stop the kinase reaction with 30 μl of Stop/Detection buffer        containing 10 mM EDTA, 1× Lance Detection Buffer (cat. #        CR97-100, PerkinElmer), 1% SuperBlocking in TBS (cat. # 37535,        Pierce), 5 nM phospho-Akt(T308) monoclonal antibody (cat. #        4056, Cell Signaling Technologies), 5 nM Lance labeled        Eu-Anti-rabbit IgG (cat. # AD0083, PerkinElmer), and 100 nM        Streptavidin-allophycocyanin conjugate (cat. # PJ25S, Prozyme).    -   5. Read HTRF signals on an Envision reader (PerkinElmer) in HTRF        mode after 60 min.    -   6. IC50 is determined by fitting the observed relationship        between compound concentration and HTRF signal with a        4-parameter logistic equation.

The compounds described in the Examples were tested in the above assayand found to have an IC₅₀≦50 μM.

While a number of embodiments of this invention have been described, itis apparent that the basic examples may be altered to provide otherembodiments, encompassed by the present invention. Therefore, it will beappreciated that the scope of this invention is to be defined by theappended claims rather than by the specific embodiments, which have beenrepresented by way of example.

1. A compound of the formula

wherein R¹ is aryl, wherein said aryl, groups is optionally substitutedwith one to three substituents independently selected from the groupconsisting of halo, hydroxyl, C₁₋₆alkyl, O(C₁₋₆alkyl), R³ and halolakyl;R² is heteroaryl, wherein said heteroaryl, group is optionallysubstituted with one to three substituents independently selected fromthe group consisting of R³, hydroxyl, cyano, halo, C₁₋₆alkyl,O(C₁₋₆alkyl), O(C₁₋₆alkyl)R³, (C₁₋₆alkyl)R³, (C═O)R³, OR³, (C═O)R³OH,(C═O)R³O(C₁₋₆alkyl), (C═O)O(C₁₋₆alkyl), R³(C═O)O(C₁₋₆alkyl), SO_(m)R³,SO_(m)R⁴, (C═O)NR⁴R⁵, (C═O)NR⁴(C₁₋₆alkyl)R³; (C═O)NR⁴(C₁₋₆alkyl)NR⁴R⁵,(C═O)O(C₁₋₆alkyl), (C═O)NR⁴SO_(m)(C₁₋₆alkyl), NR⁴R⁵, (C═O)NR⁴R⁵, N(R³)₂,NR⁴(C₁₋₆alkyl)R³, NR⁴(C═O)C₁₋₆alkyl, NR⁴SO_(m)(C₁₋₆alkyl),(C₁₋₆alkyl)NR⁴R⁵ and NHSO_(m) N(R³)₂; each R³ is independently aryl,heteroaryl, heterocyclyl or C₃₋₈cycloalkyl, wherein said aryl,heteroaryl, heterocyclyl and cycloalkyl groups are optionallysubstituted with one to three halo, hydroxyl or C₁₋₆alkyl; R⁴ ishydrogen or C₁₋₆alkyl; R⁵ is hydrogen or C₁₋₆alkyl; m is an integer fromzero to two; or a pharmaceutically acceptable salt or stereoisomerthereof.
 2. The compound of claim 1 wherein R¹ is phenyl substitutedwith two halo; or a pharmaceutically acceptable salt or stereoisomerthereof.
 3. The compound of claim 1 wherein R² is heteroaryl, whereinsaid heteroaryl group is optionally substituted with one to threesubstituents independently selected from the group consisting of R³,hydroxyl, cyano or halo; or a pharmaceutically acceptable salt orstereoisomer thereof.
 4. The compound of claim 3 wherein R² isheteroaryl, wherein said heteroaryl group is optionally substituted withone to three substituents independently selected from the groupconsisting of hydroxyl, cyano and halo; or a pharmaceutically acceptablesalt or stereoisomer thereof.
 5. The compound of claim 3 wherein R² isheteroaryl wherein said heteroaryl group is optionally substituted withone to two substituents independently selected from the group consistingof hydroxyl, cyano and halo; or a pharmaceutically acceptable salt orstereoisomer thereof.
 6. The compound which is:2-cyclopentyl-9-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluoropheny)-9-(6-chloropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;9-(5-chloropyridin-2-yl)-2-(2,6-difluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(2,6-difluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chlorophenyl)-9-pyridin-4-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chlorophenyl)-9-pyridin-3-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chlorophenyl)-9-[2(4-methylpiperazin-1-yl)pyridine-4-yl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chlorophenyl)-9-(1H-pyrazol-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chlorophenyl)-9-[4-methylpiperazin-1-yl)pyridin-3-yl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-cyclopentyl-9-(1H-pyrazol-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;9-(1H-pyrazol-3-yl)-2-(tetrahydrofuran-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;9-(1H-pyrazol-3-yl)-2-(tetrahydrofuran-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-cyclopentyl-9-(6-methoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-cyclopentyl-9-(1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-cyclopentyl-9-(2,6-dimethoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-cyclopentyl-9-pyrimidin-5-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-cyclopentyl-9-(3,5-dimethylisoxazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(1H-pyrazol-3-yl)-1,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-pyridin-3-yl-1,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(2-morpholin-4-ylpyridin-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-pyridin-4-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;9-(6-aminopyridin-3-yl)-2-(2-chloro-6-fluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(6-methoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(4-methoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-{6-[(2-morpholin-4-ylethyl)amino]pyridin-3-yl}-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(6-hydroxypyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(5-chloro-2-methoxypyridin-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(6-chloropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-[2-(cyclopropylmethoxy)pyridin-3-yl]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;p12-(2-chloro-6-fluorophenyl)-9-(6-fluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;5-[2-(2-chloro-6-fluorophenyl)-7-oxo-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-9-yl]pyridine-2-carbonitrile;2-(2-chloro-6-fluorophenyl)-9-(2,6-difluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(6-methylpyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-pyrimidin-5-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-quinolin-3-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-[6-(dimethylamino)pyridin-3-y]-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(3-furyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(2,6-dimethoxypyridin-3yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(3,5-dimethyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-isoquinolin-4-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(2-methoxypyrimidin-5-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(6-morpholin-4-ylpyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(2-methoxypyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2-chloro-6-fluorophenyl)-9-(2-fluoroquinolin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2,6-difluorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2,6-difluorophenyl)-9-(6-fluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2,6-difluorophenyl)-9-(2-fluoropyridin-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2,6-difluorophenyl)-9-(5-fluoropyridin-3-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2,6-difluorophenyl)-9-(5-fluoropyridin-2-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2,6-difluorophenyl)-9-(3-fluoropyridin-4-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;9-(2-chloropyridin-4-yl)-2-(2,6-difluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2,6-difluorophenyl)-9-(6-fluoropyridin-2-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;9-(5-chloropyridin-2-yl)-2-(2,6-difluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2,6-difluorophenyl)-9-(6-methoxypyridin-2-yl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one;2-(2,6-difluorophenyl)-9-pyridin-2-yl-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one; or a pharmaceutically acceptable salt orstereoisomer thereof.
 7. A pharmaceutical composition comprising apharmaceutically effective amount of the compound according to claims 1,and a pharmaceutically acceptable carrier.